Quinoline derivative

ABSTRACT

A compound represented by general formula (I) has a strong Axl inhibitory activity by introducing a distinctive bicyclic structure in which a saturated carbon ring is fused to a pyridone ring, and can be a therapeutic agent for Axl-related diseases, for example, cancer such as acute myeloid leukemia, melanoma, breast cancer, pancreatic cancer, and glioma, kidney diseases, immune system diseases, and circulatory system diseases.

TECHNICAL FIELD

The present invention relates to a compound represented by generalformula (I):

(wherein all of the symbols have the same meanings as given below), asalt thereof, a solvate thereof, an N-oxide thereof, or a prodrugthereof (hereinafter, also abbreviated as the compound of the presentinvention).

BACKGROUND ART

Axl (also known as: UFO, ARK, Tyro7) is a receptor tyrosine kinasebelonging to a TAM family (Axl, Mer and Tyro3) cloned from tumor cells.Gas6 (growth-arrest-specific protein 6) cloned as a gene specificallyexpressed at the time of cell proliferation arrest is known as a ligandfor Axl. Axl activated by binding of Gas6 transfers a signal viaphosphorylation. Since the signal activates an Erk1/2 pathway or aPI3K/Akt pathway, the activation of Axl is known to be involved inpathologic conditions of cancers, immune system diseases, circulatorysystem diseases, and the like (see, Non-Patent Literature 1).

In particular, the relation between Axl and various types of cancers iswell known. For example, it is known that the expression of Axl isinvolved in metastasis and prognosis of breast cancer (see, Non-PatentLiterature 2), and that Axl is involved in the pathologic conditions ofacute myeloid leukemia (AML) (see Non-Patent Literature 3). Therefore,it is considered that compounds which inhibit the activation of Axl areuseful for treatment of various type of cancers, immune system diseases,and circulatory system diseases.

By the way, as prior art of the compound of the present invention, acompound represented by general formula (A):

(wherein A^(A) represents C—R^(10A) and N; B^(A) represents C—R^(11A)and N; D^(A) represents heterocycles of the following general formulae,and the like.

(wherein R^(1A), R^(4A), and R^(88A) are independently —H, —F, —Cl, —Br,—I, —OH, —NH₂, —OCH₃, —OC₂H₅, or the like; R^(2A) and R^(3A) areindependently —R^(88A) or the like; R^(5A) and R^(6A) may be the same aseach other or different from each other, and represent —H, —F, —Cl, —Br,—I, —CN, —NO₂, —CH₃, or the like; R^(7A), R^(8A), R^(10A), and R^(11A)may be the same as each other or different from each other, andrepresent —H, —F, —Cl, —Br, —I, —CN, —NO₂, —CH₃, or the like; R^(9A)represents —H or the like; R^(12A) represents —CN, phenyl, or the like;R^(13A) represents —H, —F, —Cl, —Br, —I, —CN, —NO₂, —CH₃, or the like;R^(14A) represents —H, —F, —Cl, —Br, —I, —NO₂, —CN, or the like (wherethe definitions of the groups are excerpted)) is known to be an Axlinhibitor (see, Non-Patent Literature 1).

Furthermore, a compound represented by general formula (B):

(wherein E^(B) and G^(B) are independently a hydrogen atom, a C1-6 alkylgroup optionally substituted with one to six R^(19B), a C6-11 aryl groupoptionally substituted with one to six R^(19B) or the like; X^(B)represents N or C—R^(4B); Y^(B) represents N or C—R^(1dB); D^(B)represents —O—, —S—, —NH— or the like; W^(B) represents CH or N; R^(aB),R^(bB), R^(cB), R^(dB), R^(1aB), R^(1cB), R^(1dB) and R^(4B)independently represent a hydrogen atom, —OR^(110B), or the like;R^(19B) represents a halogen atom, —CN, or the like; and R^(110B)represents a hydrogen atom, a C1-6 alkyl group optionally substitutedwith one to six R^(129B) (where the definitions of the groups areexcerpted)) is known to be an Axl inhibitor (see Patent Literature 2).

On the other hand, a compound having a quinoline skeleton andrepresented by the following general formula (C):

is known to have an ASK1 inhibitory activity, and be an agent forpreventing and/or treating amyotrophic lateral sclerosis (ALS) (seePatent Literature 3).

Furthermore, a compound represented by general formula (D):R^(D)—X^(D)—W^(D)—Y^(D)—R^(1D)  (D)(wherein R^(D) represents

or the like; T^(D) represents phenyl or the like; Z^(D) represents N orCR^(7D); W^(D) represents a substituted or unsubstituted phenyl,substituted or unsubstituted 6-membered nitrogen-containing heteroarylor the like; X^(D) represents O, S, S(═O), or the like; Y^(D) represents—NR^(aD) C(═O)—(CR^(3D)R^(4D))_(p)— or the like; R^(aD) represents, ahydrogen atom, an alkyl group, or the like; and R^(1D) represents

or the like; J^(2D) represents O or CR^(4aD)R^(4aD); Q^(D) represents 1-to 5-membered saturated or partially unsaturated alkyl chain or thelike; R^(1D) represents optionally substituted phenyl or may be fused tooptionally substituted 5- to 6-membered heterocycle; R^(3D) and R^(4D)each independently represents a hydrogen atom, an alkyl group, an arylgroup, or the like; R^(4aD) is absent or represents a hydrogen atom, ahalogen atom, or the like (where the definitions of the groups areexcerpted)) is known to be a c-Met inhibitor (see Patent Literature 4).

Furthermore, a compound represented by general formula (E):

(wherein R^(1E), R^(2E) and R^(4E) independently represent H, F, Cl, Br,I, CN, OR^(10E) C1-C12 alkyl, or the like; L^(E) represents a C3-C12carbon ring, C6-C20 aryl, or the like; R^(5E) represents—C(═Y^(E))R^(13E), —C(═Y^(E))R^(10E)R^(13E), —NR^(10E)C(═Y^(E))R^(13E),or the like; R^(10E) represents H, C1-C12 alkyl, a C3-C12 carbon ring, aC2-C20 heterocycle, or the like; R^(13E) represents H, C1-C6 alkyl, orthe like; and Y^(E) represents O or S (where the definitions of thegroups are excerpted)) is known to be a c-Met inhibitor (see PatentLiterature 5).

However, any of the prior art literatures neither mention nor suggestthat a quinoline derivative as a compound of the present invention,having a bicyclic structure in which a saturated carbon ring is fused toa pyridone ring, represented by the following structural formula.

has a significant Axl inhibitory activity.

PRIOR ART LITERATURES Patent Literatures

-   [Patent Literature 1] WO2012/028332-   [Patent Literature 2] WO2013/074633-   [Patent Literature 3] WO2012/011548-   [Patent Literature 4] WO2006/116713-   [Patent Literature 5] WO2007/146824

Non-Patent Literatures

-   [Non-Patent Literature 1] Clinical Science, Vol. 122, p. 361-368,    2012-   [Non-Patent Literature 2] Proceedings of the national academy of    sciences of the United States of America, Vol. 107, No. 3, p.    1124-1129, 2010-   [Non-Patent Literature 3] Blood, Vol. 121, p. 2064-2073, 2013

SUMMARY OF INVENTION Technical Problem

A problem to be solved by the present invention is to find a compoundhaving an Axl inhibitory activity, which is useful for treatment ofcancer such as AML, and to provide the compound as pharmaceuticals whoseside effects are reduced.

Solution to Problem

In order to solve the above-mentioned problem, the inventors of thepresent invention have keenly studied to find a compound stronglyinhibiting Axl. As a result, surprisingly, the inventors have found thata bicyclic structure, in which a saturated carbon ring is fused to apyridone ring, represented by the following structural formula:

improves the Axl inhibitory activity, and have completed the presentinvention.

That is to say, the present invention relates to:

[1] a compound represented by general formula (I)

[wherein R¹ represents (1) a C1-8 alkyl group optionally substitutedwith one to five R¹¹, (2) a C3-7 carbon ring optionally substituted withone to five R¹², or (3) a 4- to 7-membered heterocycle optionallysubstituted with one to five R¹³, wherein when the C1-8 alkyl grouprepresented by R¹ is a branched alkyl group, the C1-3 alkyl groupbranched from the same carbon atom, together with the carbon atom boundthereto, optionally forms a saturated C3-7 carbon ring,R² represents (1) a C1-4 alkyl group, (2) a halogen atom, (3) a C1-4haloalkyl group, (4) an oxo group, (5) an —OR²¹ group, or (6) an ═NR²²group,R³ represents (1) a C1-4 alkyl group, (2) a halogen atom, or (3) a C1-4haloalkyl group,R⁴ represents (1) a C1-4 alkoxy group, (2) a C1-4 haloalkyl group, (3)an —OR⁴¹ group, (4) a C1-4 alkyl group, (5) a C2-4 alkenyloxy group, or(6) a C2-4 alkynyloxy group,R⁵ represents (1) a hydrogen atom, (2) a C1-4 alkyl group, (3) a halogenatom, (4) a C1-4 haloalkyl group, or (5) an —OR²¹ group,R¹¹ represents (1) an —OR¹⁰¹ group, (2) an SO₂R¹⁰² group, (3) anNR¹⁰³R¹⁰⁴ group, or (4) a C3-7 carbon ring optionally substituted withone to three halogen atoms,R¹² represents (1) a C1-8 alkyl group optionally substituted with ahydroxyl group, or (2) a halogen atom,R¹³ represents (1) a C1-8 alkyl group optionally substituted with ahydroxyl group, or (2) a halogen atom,R²¹ represents (1) a hydrogen atom, or (2) a C1-4 alkyl group,R²² represents (1) a hydroxyl group, or (2) C1-4 alkoxy group,R⁴¹ represents

(1) a hydrogen atom;

(2) a C1-8 alkyl group substituted with one to two substituents selectedfrom the group consisting of (a) 5- to 7-membered cyclic groupoptionally substituted with one to two substituents selected from thegroup consisting of (i) a C1-4 alkyl group, (ii) a C1-4 haloalkyl group,and (iii) a halogen atom, (b) NR⁴⁰¹R⁴⁰², (c) a hydroxyl group, and (d)an SO₂R⁴⁰³ group;

(3) a C2-8 alkenyl group substituted with one to two substituentsselected from the group consisting of (a) 5- to 7-membered cyclic groupoptionally substituted with one to two substituents selected from thegroup consisting of (i) a C1-4 alkyl group, (ii) a C1-4 haloalkyl group,and (iii) a halogen atom, (b) NR⁴⁰¹R⁴⁰², (c) a hydroxyl group, and (d)an SO₂R⁴⁰³ group; or

(4) a C2-8 alkynyl group substituted with one to two substituentsselected from the group consisting of (a) 5- to 7-membered cyclic groupoptionally substituted with one to two substituents selected from thegroup consisting of (i) a C1-4 alkyl group, (ii) a C1-4 haloalkyl group,and (iii) a halogen atom, (b) NR⁴⁰¹R⁴⁰², (c) a hydroxyl group, and (d)an SO₂R⁴⁰³ group,

R¹⁰¹ represents (1) a hydrogen atom, or (2) a C1-4 alkyl group,

R¹⁰² represents (1) a hydrogen atom, or (2) a C1-4 alkyl group,

R¹⁰³ and R¹⁰⁴ each independently represents (1) a hydrogen atom, or (2)a C1-4 alkyl group,

R⁴⁰¹ and R⁴⁰² each independently represents (1) a hydrogen atom, or (2)a C1-4 alkyl group,

R⁴⁰³ represents (1) a hydrogen atom, or (2) a C1-4 alkyl group,

A represents (1) CH, or (2) a nitrogen atom,

L represents (1) —O—, (2) —NH—, (3) —C(O)—, (4) —CR⁶R⁷—, (5) —S—, (6)—S(O)—, or (7) —S(O)₂—,

R⁶ and R⁷ each independently represents (1) a hydrogen atom, (2) ahalogen atom, (3) a C1-4 alkyl group, (4) a hydroxyl group, or (5) NH₂,

ring1 represents a 5- to 7-membered cyclic group,

represents a single bond or a double bond,

m is an integer from 0 to 5,

n is an integer from 0 to 5,

p is an integer from 0 to 2,

q is an integer from 0 to 4,

when m is two or more, a plurality of R² may be the same as or differentfrom each other, and when two of R² represent a C1-3 alkyl group and areon the same carbon atom, the R², together with a carbon atom boundthereto, may form a saturated C3-7 carbon ring,when n is two or more, a plurality of R³ may be the same as or differentfrom each other, andwhen q is two or more, a plurality of R⁴ may be the same as or differentfrom each other], a salt thereof, a solvate thereof, an N-oxide thereof,or a prodrug thereof,[2] the compound according to the above-mentioned [1], wherein m is oneor more, and one of two R² is necessarily an oxo group,[3] the compound according to the above-mentioned [1] or [2], whereinthe ring1 is benzene or pyridine,[4] the compound according to any one of the above-mentioned [1] to [3],wherein L is (1) —O—, (2) —NH—, or (3) —C(O)—,[5] the compound according the above-mentioned [1], which is representedby general formula (I-1)

[wherein R²⁻¹ represents (1) a C1-4 alkyl group, (2) a halogen atom, (3)a C1-4 haloalkyl group, (4) an —OR²¹ group, or (5) an ═NR²² group,m-1 is an integer from 0 to 4,L¹ is (1) —O—, (2) —NH—, or (3) —C(O)—,ring1-1 represents benzene or pyridine, when m-1 is two or more, aplurality of R²⁻¹ may be the same as or different from each other, andwhen two of R²⁻¹ represent a C1-3 alkyl group and are on the same carbonatom, the R²⁻¹, together with a carbon atom bound thereto, may form asaturated C3-7 carbon ring,and other symbols have the same meanings as defined in theabove-mentioned [1]],[6] the compound according to any one of the above-mentioned [1] to [5],which is: (1)

-   N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (2)-   N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-7,7-dimethyl-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (3)-   N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2,2-dimethylpropyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (4)-   N-[5-({7-[3-(4-morpholinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (5)-   N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3-fluorophenyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (6)-   N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (7)-   N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (8)-   N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(3-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (9)-   N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (10)-   N-{5-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (11)-   N-{5-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-pyridinyl}-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (12)-   N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[(2S)-1-hydroxy-3-methyl-2-butanyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (13)-   N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3-fluorophenyl}-1-(3-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (14)-   N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-6,6-dimethyl-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (15)-   N-[5-({6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (16)-   N-(5-{[7-(3-hydroxy-3-methylbutoxy)-6-methoxy-4-quinolinyl]oxy}-2-pyridinyl)-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    or (17)-   N-[5-({6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-di    oxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    [7] a pharmaceutical composition containing a compound represented    by general formula (I) as defined in the above-mentioned [1], a salt    thereof, a solvate thereof, an N-oxide thereof, or a prodrug    thereof,    [8] the pharmaceutical composition according to the above-mentioned    [7], which is an Axl inhibitor,    [9] the pharmaceutical composition according to the above-mentioned    [7], which is an agent for preventing and/or treating an Axl-related    disease,    [10] the pharmaceutical composition according to the above-mentioned    [9], wherein the Axl-related diseases includes cancer, kidney    diseases, immune system diseases, or circulatory system diseases,    [11] the pharmaceutical composition according to the above-mentioned    [10], wherein the cancer is acute myeloid leukemia, chronic myeloid    leukemia, acute lymphatic leukemia, melanoma, breast cancer,    pancreatic cancer, glioma, esophageal adenocarcinoma, large    intestine cancer, renal cell carcinoma, thyroid cancer, non-small    cell lung cancer, prostate cancer, stomach cancer, liver cancer,    uveal malignant melanoma, ovarian cancer, endometrial cancer,    lymphoma, head and neck cancer, or sarcoma,    [12] the pharmaceutical composition according to the above-mentioned    [7], which is a metastasis suppressing agent for cancer cells,    [13] a method for preventing and/or treating an Axl-related disease,    the method including administering an effective amount of a compound    represented by general formula (I) as defined in the above-mentioned    [1], a salt thereof, a solvate thereof, an N-oxide thereof, or a    prodrug thereof, to a mammal,    [14] a compound represented by general formula (I) according to the    above-mentioned [1], a salt thereof, a solvate thereof, an N-oxide    thereof, or a prodrug, for preventing and/or treating an Axl-related    disease, and    [15] use of a compound represented by general formula (I), a salt    thereof, a solvate thereof, an N-oxide thereof, or a prodrug, as    defined in the above-mentioned [1], to manufacture an agent for    preventing and/or treating an Axl-related disease.

Effects of Invention

A compound of the present invention has a strong Axl inhibitoryactivity, has an Axl-selective inhibitory activity to a specific kinase,and has reduced CYP inhibitory effect, and therefore is useful as atherapeutic drug for acute myeloid leukemia or the like, has less sideeffect and has little concern about drug interaction.

DESCRIPTION OF EMBODIMENTS

The present invention will be described in detail hereinafter.

In the present invention, a halogen atom denotes a fluorine atom, achlorine atom, a bromine atom, and an iodine atom.

In the present invention, the C1-8 alkyl group includes a straight orbranched C1-8 alkyl group. Examples thereof include methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl,sec-butyl, tert-butyl, and an isomer thereof.

In the present invention, the C1-4 alkyl group includes a straight orbranched C1-4 alkyl group. Examples thereof include methyl, ethyl,propyl, butyl, isopropyl, isobutyl, sec-butyl, and tert-butyl.

In the present invention, the C1-3 alkyl group includes a straight orbranched C1-3 alkyl group. Examples thereof include a methyl group, anethyl group, a propyl group, and an isopropyl.

In the present invention, the C1-4 haloalkyl group denotes, for example,a fluoromethyl group, a chloromethyl group, a bromomethyl group, aniodomethyl group, a difluoromethyl group, a trifluoromethyl group, a1-fluoroethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, apentafluoroethyl group, a 1-fluoropropyl group, a 2-chloropropyl group,a 3-fluoropropyl group, a 3-chloropropyl group, a 4,4,4-trifluorobutylgroup, and a 4-bromobutyl group.

In the present invention, the C2-8 alkenyl group denotes, for example, avinyl group, a propenyl group, a butenyl group, a pentenyl group, ahexenyl group, a heptenyl group, and a octenyl group, and an isomerthereof, and the like.

In the present invention, the C2-8 alkynyl group denotes, for example,an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, ahexynyl group, a heptynyl group, an octynyl group, and an isomerthereof.

In the present invention, examples of the C1-4 alkoxy group include amethoxy group, an ethoxy group, a propoxy group, an isopropoxy group, abutoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxygroup.

In the present invention, the C2-4 alkenyloxy group denotes, forexample, vinyloxy, propenyloxy, butenyloxy, and an isomer thereof.

In the present invention, the C2-4 alkynyloxy group denotes, forexample, ethynyloxy, propynyloxy, butynyloxy, and an isomer thereof.

In the present invention, the C3-7 carbon ring denotes a C3-7 monocycliccarbon ring, and a carbon ring which may be partially or completelysaturated, and examples thereof include cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclobutene, cyclopentene,cyclohexene, cycloheptene, cyclobutadiene, cyclopentadiene,cyclohexadiene, cycloheptadiene, or benzene ring.

In the present invention, the C5-7 carbon ring denotes a C5-7 monocycliccarbon ring, and a carbon ring which may be partially or completelysaturated, and examples thereof include cyclopentane, cyclohexane,cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene,cyclohexadiene, cycloheptadiene, or benzene ring.

In the present invention, examples of the saturated C3-7 carbon ringinclude cyclopropane, cyclobutane, cyclopentane, cyclohexane, andcycloheptane.

In the present invention, the 4- to 7-membered heterocycle denotes 4- to7-membered monocyclic heterocycle, which includes one to fiveheteroatoms selected from an oxygen atom, a nitrogen atom and a sulfuratom, and a part or all of which is saturated. Example thereof includeazetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine,triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline,pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine,dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine,tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine,tetrahydropyridazine, perhydropyridazine, dihydroazepine,tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxetan, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thietane, dihydrothiophene,tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran,dihydrothiepin, tetrahydrothiepin, perhydrothiepin, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole, (oxadiazolidine), dihydrooxazine,tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine,dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine),dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine,tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepin, tetrahydrothiadiazepin,perhydrothiadiazepin, morpholine, thiomorpholine, oxathiane, dioxolane,dioxane, dithiolane, dithiane, pyrrole, imidazole, triazole, tetrazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine,diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepin, oxazole,isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine,oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine,thiazepine, or thiadiazepin ring.

In the present invention, the 5- to 7-membered cyclic group denotes C5-7carbon ring and 5- to 7-membered heterocycle. Herein, the C5-7 carbonring has the same meaning as defined above, the 5- to 7-memberedheterocycle includes 5- to 7-membered unsaturated heterocycle and 5- to7-membered saturated heterocycle. Examples of 5- to 7-memberedheterocycle include pyrroline, pyrrolidine, imidazoline, imidazolidine,triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline,pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine,dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine,tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine,tetrahydropyridazine, perhydropyridazine, dihydroazepine,tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran,dihydropyran, tetrahydropyran, dihydrooxepine, tetrahydrooxepine,perhydrooxepine, dihydrothiophene, tetrahydrothiophene,dihydrothiopyran, tetrahydrothiopyran, dihydrothiepin,tetrahydrothiepin, perhydrothiepin, dihydrooxazole, tetrahydrooxazole(oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole,(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepin,tetrahydrothiadiazepin, perhydrothiadiazepin, morpholine,thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithiane,pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin,thiophene, thiopyran, thiepin, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, orthiadiazepin ring.

In the present invention, the 6-membered cyclic group denotes C6 carbonring and 6-membered heterocycle. Examples thereof include cyclohexane,cyclohexene, cyclohexadiene, benzene, pyridine, pyrazine, pyrimidine,pyridazine, pyran, thiopyran, oxazine, oxadiazine, thiazine,thiadiazine, dihydropyridine, tetrahydropyridine, piperidine,dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine,tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine,tetrahydropyridazine, perhydropyridazine, dihydropyran, tetrahydropyran,dihydrothiopyran, tetrahydrothiopyran, dihydrooxazine,tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine,tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxane,and dithiane ring.

In the present invention, “when the C1-8 alkyl group represented by R¹is a branched alkyl group, the C1-3 alkyl group branched from the samecarbon atom optionally forms a saturated C3-7 carbon ring together”denotes that in a partial structure of the following general formula(I):

(wherein all of the symbols have the same meanings as defined above),for example, when R¹ is a branched alkyl chain as represented in theabove-mentioned general formula, the alkyl chain branched from the samecarbon atom, together with the carbon atom bound thereto, forms asaturated carbon ring, as shown in the following general formula:

(wherein all of the symbols have the same meanings as defined above).

In the present invention, “when two of R² represent a C1-3 alkyl groupand are on the same carbon atom, the R², together with a carbon atombound thereto, may form a saturated C3-7 carbon ring” denotes that in apartial structure of the following general formula (I):

(wherein all of the symbols have the same meanings as defined above),for example, when R² is an alkyl group as represented in theabove-mentioned general formula and are on the same carbon atom, the R²,together with a carbon atom bound thereto, forms a saturated carbonring, as shown in the following general formula:

(wherein all of the symbols have the same meanings as defined above).

In the present invention, “when two of R²⁻¹ represent a C1-3 alkyl groupand are on the same carbon atom, the R²⁻¹, together with a carbon atombound thereto, may form a saturated C3-7 carbon ring” has the samedefinition as that for R² in the phrase: “when two of R² represent aC1-3 alkyl group and are on the same carbon atom, the R², together witha carbon atom bound thereto, may form a saturated C3-7 carbon ring.”

In the present invention, it is preferable that m is one or more, andone of R² is necessarily an oxo group.

In the present invention, it is preferable that A is CH.

In the present invention, it is preferable that R⁴ is a C1-4 alkoxygroup or an —OR⁴¹ group.

In the present invention, it is preferable that L is —O—, —NH—, or—C(O)—.

In the present invention, ring1 is preferably a 6-membered cyclic group,and more preferably benzene or pyridine.

In the present invention, it is preferable that the compound representedby general formula (I) is a compound represented by general formula(I-1):

(wherein all of the symbols have the same meanings as defined above).

In the present invention, it is preferable that two binding arms in thering1 and ring1-1 are bound to a para position.

In the present invention, in general formula (I-1), A is preferably CH,and R⁴ is preferably a C1-4 alkoxy group or an —OR⁴¹ group.

In the present invention, preferable compounds preferably include thecompounds described in Examples, and the following (1) to (17) are morepreferable:

-   (1)    N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,-   (2)    N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-7,7-dimethyl-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,-   (3)    N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2,2-dimethylpropyl)-2,5-di    oxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide, (4)-   N-[5-({7-[3-(4-morpholinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (5)-   N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3-fluorophenyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (6)-   N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (7)-   N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (8)-   N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(3-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (9)-   N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (10)-   N-{5-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (11)-   N-{5-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-pyridinyl}-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (12)-   N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[(2S)-1-hydroxy-3-methyl-2-butanyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (13)-   N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3-fluorophenyl}-1-(3-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (14)-   N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-6,6-dimethyl-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (15)-   N-[5-({6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (16)-   N-(5-{[7-(3-hydroxy-3-methylbutoxy)-6-methoxy-4-quinolinyl]oxy}-2-pyridinyl)-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,    (17)-   N-[5-({6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide.    [Isomer]

In the present invention, unless specifically directed, all of theisomers are included. For example, an alkyl group includes straightchain and branched chain groups. In addition, all of geometrical isomersof double bonds, rings, and fused rings (E-, Z-, cis-, trans-isomers),optical isomers by the presence of an asymmetric carbon atom (R-,S-isomer, α-, β-configurations, enantiomers, diastereomers), opticalactive isomers having optical rotation property (D, L, d, 1-isomers),polar isomers according to chromatographic separation (more polarisomer, less polar isomer), equilibrium compound, rotamers, mixturesthereof at any rate, and racemic mixtures are included in the presentinvention. Furthermore, the present invention also encompasses allisomers by tautomers.

Furthermore, the optical isomer of the present invention is not onlylimited to an optical isomer having purity of 100%, but also may includeother optical isomers having purity of less than 50%.

In the present invention, unless otherwise noted, as apparent to aperson skilled in the art, a symbol:

represents binding toward the back side of the plane of the paper (thatis to say, the α-configuration),

represents binding toward the front side of the plane of the paper (thatis to say, the β-configuration), and

represents α-configuration, β-configuration or an arbitrary mixturethereof.

The compound represented by general formula (I) is converted into acorresponding salt by the well-known method. A salt is preferably awater-soluble salt. Examples of a suitable salt include salts of analkali metal (potassium, sodium, and the like), salts of an alkalineearth metal (calcium, magnesium, and the like), ammonium salts, or saltsof a pharmaceutically acceptable organic amine (tetramethylammonium,triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine,N-methyl-D-glucamine, and the like), acid addition salts (inorganic acidsalts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate,nitrate, and the like), organic acid salts (acetate, trifluoro acetate,lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate,methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate,isethionate, glucuronate, gluconate, and the like).

The compound represented by general formula (I) and a salt thereof canbe also converted into a solvate. It is preferable that the solvate islow-toxic and water-soluble. Examples of a suitable solvate includesolvates with water, or an alcoholic solvent (for example, ethanol).

The N-oxide of the compound represented by general formula (I) denotescompounds represented by general formula (I) in which a nitrogen atom isoxidized. Furthermore, the N-oxide of the compound represented bygeneral formula (I) may be salts of alkali (earth) metal salt, ammoniumsalt, organic amine salt, and acid addition salt mentioned above.

The prodrug of the compound represented by general formula (I) denotes acompound which is converted to a compound represented by general formula(I) by a reaction with an enzyme, stomach acid, and the like, in aliving body. Prodrugs of the compound represented by general formula (I)include: compounds in which the hydroxyl group is acylated, alkylated,phosphorylated, or borated, when the compounds represented by generalformula (I) have a hydroxyl group (for example, the compoundsrepresented by general formula (I) in which the hydroxyl group isacetylated, palmitoylated, propanoylated, pivaloylated, succinylated,fumarylated, alanylated, or dimethylaminomethylcarbonylated); andcompounds in which the carboxyl group is esterified or amidated (forexample, compounds represented by general formula (I) in which thecarboxyl group is made into ethyl ester, isopropyl ester, phenyl ester,carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester,ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester, methylamide, and the like). Thesecompounds can be produced by well-known methods. Furthermore, theprodrug of the compound represented by general formula (I) may behydrate or non-hydrate. Furthermore, the prodrug of the compoundrepresented by general formula (I) may be a compound which is changedinto the compound represented by general formula (I) under thephysiological condition, as described in “Development of Medicaments”,vol. 7 “Molecular Design”, p. 163-198, published by Hirokawa Shoten in1990. In addition, the compound represented by general formula (I) maybe labeled with an isotope thereof (for example, ²H, ³H, ¹¹C, ¹³C, ¹⁴C,¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, ¹²⁵I, and the like).

[Process for Producing Compound of the Present Invention]

The compound of the present invention can be produced by the well-knownmethods, for example, the method described in Comprehensive OrganicTransformations: A Guide to Functional Group Preparations, 2nd Edition(Richard C. Larock, John Wiley & Sons Inc, 1999), or methods describedin Examples, or the like, with appropriate modification and incombination thereof.

A compound represented by general formula (I) wherein L is an oxygenatom, and R² is an oxo group, that is, a compound represented by generalformula (I-A):

(wherein all of the symbols have the same meanings as defined above) canbe produced by the process represented by the following reaction processschemes 1 and 2:

(wherein each of X¹ and X² independently represents a halogen atom, X¹and X² may be the same as or different from each other, and the othersymbols have the same meanings as defined above).

In the reaction process scheme 1, the reaction 1 can be carried out bysubjecting a compound represented by general formula (a) and a compoundrepresented by general formula (II) to the aromatic nucleophilicsubstitution reaction. The aromatic nucleophilic substitution reactionis well known, and is carried out, for example, in an organic solvent(chlorobenzene, N,N-dimethyl sulfoxide, N,N-dimethyl acetamide,N,N-dimethylformamide, chloroform, dichloromethane, diethyl ether,tetrahydrofuran, methyl t-butyl ether, and the like), in the presence orabsence of a catalyst (4-dimethylaminopyridine (DMAP) and the like), andin the presence or absence of a base (sodium hydride, triethylamine,cesium carbonate, and the like), at 0 to 200° C.

In the reaction process scheme 1, the reaction 2 is carried out byreacting a compound represented by general formula (b) in an organicsolvent (tetrahydrofuran, and the like), in the presence of a palladiumcatalyst (tris(dibenzylideneacetone)dipalladium(0) chloroform complex,and the like), in the presence of a base (lithiumbis(trimethylsilyl)amide (LHMDS), potassium bis(trimethylsilyl)amide(KHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), and the like), aphosphine compound (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl(S-Phos), tri-tert-butylphosphine (P(t-Bu)₃), and the like) at 0 to 100°C., and then reacting by adding inorganic acid (hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid,nitric acid, and the like) at 0 to 150° C. Alternatively, the productionmethod for aryl amine described in Organic Letters, Vol 3, No. 17, p.2729-2732, 2001 can be employed.

(wherein R^(d) represents a C1-4 alkyl group, and the other symbols havethe same meanings as defined above).

In the reaction process scheme 2, the reaction 3 is carried out by areaction of a compound represented by general formula (d) and a compoundrepresented by general formula (III). The reaction is well known, and,for example, can be carried out at 0 to 100° C. in an organic solvent(N,N-dimethyl formamide and the like), in the presence of a base(tert-butoxy potassium and the like).

In the reaction process scheme 2, the reaction 4 can be carried out bysubjecting a compound represented by general formula (e) and a compoundrepresented by general formula (IV) to addition reaction. The reactionis well known, and, for example, can be carried out by reacting at 0 to100° C. in an alcohol solvent (methanol, ethanol, and the like).

In the reaction process scheme 2, the reaction 5 can be carried out byusing and subjecting the compound represented by general formula (c) andthe compound represented by general formula (f) to an amidationreaction. The amidation reaction is well known, and examples thereofinclude:

(1) a method using an acid halide,

(2) a method using a mixed acid anhydride, and

(3) a method using a condensing agent.

These methods are specifically described below:

(1) The method using an acid halide is carried out, for example, byreacting a carboxylic acid with an acid halogenating agent (oxalylchloride, thionyl chloride, and the like) in an organic solvent(chloroform, dichloromethane, diethyl ether, tetrahydrofuran, and thelike) at −20° C. to reflux temperature, and then reacting the obtainedacid halide in the presence of a base (pyridine, triethylamine,dimethylaniline, dimethylaminopyridine, diisopropylethylamine, and thelike) in amine and an organic solvent (chloroform, dichloromethane,diethyl ether, tetrahydrofuran, and the like) at 0 to 40° C.Additionally, the method can be also carried out by reacting theobtained acid halide with an amine at 0 to 40° C. by using an alkalineaqueous solution (sodium bicarbonate water or sodium hydroxide solution,and the like) in an organic solvent (dioxane, tetrahydrofuran, and thelike).

(2) The method using a mixed acid anhydride is carried out, for example,by reacting carboxylic acid with an acid halide (pivaloyl chloride,tosyl chloride, mesyl chloride, and the like) or an acid derivative(ethyl chloroformate, isobutyl chloroformate, and the like) in thepresence of a base (pyridine, triethylamine, dimethylaniline,dimethylaminopyridine, diisopropylethylamine, and the like) in anorganic solvent (chloroform, dichloromethane, diethyl ether,tetrahydrofuran, and the like) or in the absence of any solvent at 0 to40° C., and then reacting the obtained mixed acid anhydride with aminein an organic solvent (chloroform, dichloromethane, diethyl ether,tetrahydrofuran, and the like) at 0 to 40° C.

(3) The method using a condensing agent is carried out, for example, byreacting a carboxylic acid with an amine in an organic solvent(chloroform, dichloromethane, dimethyl formamide, diethyl ether,tetrahydrofuran, and the like) or in the absence of any solvent at 0 to40° C. in the presence or absence of a base (diisopropylethylamine(DIPEA), pyridine, triethylamine, dimethylaniline,dimethylaminopyridine, and the like), using a condensing agent(O-(7-Aza-1-benzotriazolyl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), (1,3-dicyclohexylcarbodiimide (DCC),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridiniumiodine,1-propylphosphonic acid cyclic anhydride (PPA), and the like) and using,or not using, 1-hydroxybenztriazole (HOBt).

These reactions (1), (2), and (3) are desirably carried out under aninert gas (argon, nitrogen, etc.) atmosphere in anhydrous conditions.

Furthermore, the compound represented by general formula (c) can be alsoproduced by the reaction process scheme 3.

(wherein all of the symbols have the same meanings as defined above).

In the reaction process scheme 3, a compound represented by generalformula (b)′ can be produced by the same method as in theabove-mentioned reaction 1 using a compound represented by generalformula (a)′ and the compound represented by general formula (V).

In the reaction process scheme 3, the reaction 6 can be carried out bysubjecting the compound represented by general formula (b)′ to areduction reaction of the nitro group. The reduction reaction of a nitrogroup is well known, and can be carried out by, for example, thefollowing method.

(1) The reduction reaction is carried out in, for example, a solvent[ethers (tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether,etc.), alcohols (methanol, ethanol, and the like), benzenes (benzene,toluene, and the like), ketones (acetone, methyl ethyl ketone, and thelike), nitriles (acetonitrile, and the like), amides (dimethylformamide,and the like), water, ethyl acetate, acetic acid or a mixture solvent oftwo or more thereof] in the presence of a hydrogeneration catalyst(palladium-carbon, palladium black, palladium, palladium hydroxide,platinum dioxide, platinum-carbon, nickel, Raney-nickel, rutheniumchloride, etc.), in the presence or absence of acids (hydrochloric acid,sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid,acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid,formic acid, and the like), at normal pressure or reduced pressure undera hydrogen atmosphere, in the presence of formic acid ammonium or in thepresence of hydrazine, at 0 to 200° C.

(2) The reaction is carried out, for example, in a water-misciblesolvent (ethanol, methanol, tetrahydrofuran, etc.) in the presence orabsence of an acid (hydrochloric acid, hydrobromic acid, ammoniumchloride, acetic acid, ammonium formate, etc.) using a metal reagent(zinc, iron, tin, tin chloride, iron chloride, samarium, indium, sodiumborohydride-Nickel chloride, etc.) at 0 to 150° C.

In the reaction process schemes 1 to 3, when a compound represented byeach general formula includes a protective group, a deprotectionreaction can be carried out if necessary. The deprotection reaction ofthe protective group is known, and can be carried out by the methodsmentioned below. Examples thereof include: (1) deprotection reactions byalkaline hydrolysis, (2) deprotection reaction in acidic conditions, (3)deprotection reaction by hydrogenolysis, (4) deprotection reaction of asilyl group, (5) deprotection reaction using metal, (6) deprotectionreaction using a metal complex, and the like.

These methods are specifically described:

(1) The deprotection reaction by alkaline hydrolysis condition iscarried out, for example, in an organic solvent (for example, methanol,tetrahydrofuran, dioxane, etc.) with hydroxide of alkaline metal (forexample, sodium hydroxide, potassium hydroxide, lithium hydroxide,etc.), hydroxide of alkaline earth metal (for example, barium hydroxide,calcium hydroxide, and the like), or carbonate (for example, sodiumcarbonate or potassium carbonate, and the like), or an aqueous solutionthereof or a mixture thereof at 0 to 40° C.

(2) The deprotection reaction in acidic conditions is carried out, forexample, in an organic solvent (for example, dichloromethane,chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol,tetrahydrofuran, anisole, etc.), organic acid (for example, acetic acid,trifluoroacetic acid, methanesulfonic acid, p-tosyl acid, etc.), orinorganic acid (for example, hydrochloric acid, sulfuric acid, etc.), ora mixture thereof (for example, hydrogen bromide/acetic acid, etc.) inthe presence or absence of 2,2,2-trifluoroethanol at 0 to 100° C.

(3) The deprotection reaction by hydrogenolysis is carried out, forexample, in a solvent (for example, ethers (tetrahydrofuran, dioxane,dimethoxyethane, diethyl ether, etc.), alcohols (for example, methanol,ethanol, and the like), benzenes (for example, benzene, toluene, etc.),ketones (for example, acetone, methyl ethyl ketone, and the like),nitriles (for example, acetonitrile, and the like), amides (for example,N,N-dimethylformamide, and the like), water, ethyl acetate, acetic acid,or a mixture of two or more thereof, etc.) in the presence of a catalyst(for example, palladium-carbon, palladium black, palladiumhydroxide-carbon, platinum oxide, Raney nickel, etc.) under hydrogenatmosphere at normal pressure or elevated pressure, or in the presenceof ammonium formate at 0 to 200° C.

(4) The deprotection reaction of a silyl group is carried out, forexample, in a water-miscible organic solvent (for example,tetrahydrofuran, acetonitrile, and the like), by usingtetrabutylammonium fluoride at 0 to 40° C. The reaction is also carriedout, for example, in organic acid (for example, acetic acid,trifluoroacetic acid, methanesulfonic acid, p-tosyl acid, etc.), or ininorganic acid (for example, hydrochloric acid, sulfuric acid, and thelike) or a mixture thereof (for example, hydrogen bromide/acetic acid,and the like) at −10 to 100° C.

(5) The deprotection reaction using a metal is carried out, for example,in an acidic solvent (for example, acetic acid, a buffer of pH 4.2 to7.2, a mixed solution of the solution and an organic solvent such astetrahydrofuran, etc.) in the presence of powder zinc, if necessary,with an ultrasonic wave applied at 0 to 40° C.

(6) The deprotection reaction using a metal complex is carried out, forexample, in an organic solvent (for example, dichloromethane,N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile,dioxane, ethanol, etc.), water or a mixed solvent thereof in thepresence of a trap reagent (for example, tributyltin hydride,triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.),an organic acid (for example, acetic acid, formic acid, 2-ethylhexanicacid, etc.) and/or in the presence of an organic acid salt (for example,sodium 2-ethylhexanate, potassium 2-ethylhexanate, and the like) in thepresence or absence of a phosphine reagent (for example,triphenylphosphine, and the like) using a metal complex (for example,tetrakis(triphenylphosphine)palladium(O),dichlorobis(triphenylphosphine)palladium (II), palladium acetate (II),chlorotris(triphenylphosphine)rhodium (I), etc.) at 0 to 40° C.

In addition to the above-mentioned methods, the deprotection reactioncan be carried out by the method described in for example, T. W. Greene,Protective Groups in Organic Synthesis, Wiley, New York, 1999.

Examples of a protective group for a hydroxyl group include a methylgroup, a trityl group, a methoxymethyl (MOM) group, a 1-ethoxyethyl (EE)group, a methoxyethoxymethyl (MEM) group, a 2-tetrahydropyranyl (THP)group, a trimethylsilyl (TMS) group, a triethylsilyl (TES) group, at-butyldimethylsilyl (TBDMS) group, a t-butyldiphenylsilyl (TBDPS)group, an acetyl (Ac) group, a pivaloyl group, a benzoyl group, a benzyl(Bn) group, a p-methoxybenzyl group, an allyloxycarbonyl (Alloc) group,a 2,2,2-trichloroethoxycarbonyl (Troc) group, and the like.

Examples of a protective group for an amino group include abenzyloxycarbonyl group, a t-butoxycarbonyl group, an allyloxycarbonyl(Alloc) group, a 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, atrifluoroacetyl group, a 9-fluororenylmethoxycarbonyl group, a benzyl(Bn) group, a p-methoxybenzyl group, a benzyloxymethyl (BOM) group, a2-(trimethylsilyl)ethoxymethyl (SEM) group, and the like.

The protective groups for a hydroxyl group and an amino group are notparticularly limited to the above-described groups, and groups areincluded, in addition to the above-mentioned groups, as long as thegroups can be detached easily and selectively. For example, thosedescribed in Protective Groups in Organic Synthesis (T. W. Greene, JohnWiley & Sons Inc., 1999) may be used.

In each reaction in the present specification, compounds used asstarting raw material, for example, the compound represented by generalformula (a), (a)′, (d), (II), (III), (IV) or (V) is well known or can beproduced by well-known methods.

In each reaction in the present specification, as apparent to theskilled persons in the art, the reactions involving heating can becarried out using a water bath, an oil bath, a sand bath or a microwave.

In each reaction in the present specification, a solid-supported reagentwhich is supported on a high molecular polymer (e.g., polystyrene,polyacrylamide, polypropylene, polyethylene glycol, etc.) may beappropriately used.

In each reaction in the present specification, the reaction products canbe purified by conventional purification methods, for example, bydistillation at normal or reduced pressure, by high performance liquidchromatography using silica gel or magnesium silicate, thin layerchromatography, ion-exchange resin, scavenger resin, or columnchromatography, washing, recrystallization, or the like. Thepurification may be done after each reaction or after several reactions.

[Toxicity]

The toxicity of the compound of the present invention is sufficientlylow, and the compound can be safely used as pharmaceuticals.

[Application to Pharmaceuticals]

Since the compound of the present invention has an Axl inhibitoryactivity, it can be used as an agent for preventing and/or treating anAxl-related disease in mammals, especially in human.

In the present invention, examples of the Axl-related diseases includecancer, kidney diseases, immune system disease, and circulatory systemdisease.

In the present invention, the cancer includes acute myeloid leukemia,chronic myeloid leukemia, acute lymphatic leukemia, melanoma, breastcancer, pancreatic cancer, glioma, esophageal adenocarcinoma, largeintestine cancer, renal cell carcinoma, thyroid cancer, non-small celllung cancer, prostate cancer, stomach cancer, liver cancer, uvealmalignant melanoma, ovarian cancer, endometrial cancer, lymphoma, headand neck cancer, and sarcoma.

In the present invention, examples of the kidney diseases includeglomerular nephritis, chronic nephritis, IgA nephritis, sequential(secondary) nephritis, nephrosis nephritis, acute renal failure, chronicrenal failure, diabetic nephropathy, gouty nephropathy, interstitialnephritis, and nephropyelitis.

In the present invention, examples of the immune system disease includepsoriasis, and rheumatoid arthritis.

In the present invention, examples of the circulatory system diseaseinclude atherosclerosis and thrombosis.

Furthermore, since the compound of the present invention has an Axlinhibitory activity, it can be used as a metastasis suppressing agent tocancer cell.

The compound of the present invention may be administered as acombination drug in combination with other drugs in order to accomplishthe following purposes:

1) to supplement and/or enhance the preventive and/or therapeutic effectof the compound;

2) to improve the kinetics, improvement of absorption, and reduction ofthe dose of the compound; and/or

3) to eliminate the side effects of the compound.

A combination drug of the compound of the present invention and otherdrugs may be administered in the form of a compounding agent includingthese components mixed into one formulation, or may be administered inseparate formulations. Administration as separate formulations includessimultaneous administration and administration at different times. Inthe administration at different times, the compound of the presentinvention may be administered before the other drug. Alternatively, theother drug may be administered before the compound of the presentinvention. The method for the administration of these drugs may be thesame as each other or different from each other.

Diseases on which the preventive and/or therapeutic effect of theabove-mentioned combination drug works are not particularly limited butmay be those in which the preventive and/or therapeutic effect of thecompound of the present invention is supplemented and/or enhanced.

The other drugs for supplementing and/or enhancing the preventive and/ortherapeutic effect of the compound of the present invention againstcancer include, for example, alkylating agents, antimetabolites,anticancer antibiotics, plant alkaloids, hormones, platinum compounds,anti-CD20 antibodies, anti-CD52 antibodies, anti-PD-1 antibodies, G-CSFformulations, acute promyelocytic leukemia differentiation-inducingagents, kinase inhibitors, topoisomerase inhibitors, aromataseinhibitors, and other anticancer drugs.

The other drug for supplementing and/or enhancing the preventive and/ortherapeutic effect of the compound of the present invention againstkidney diseases include, for example, steroids, immunosuppressants,angiotensin II antagonistic drugs, angiotensin-converting enzymeinhibitors, antiplatelet drugs, and anticoagulant drugs.

The other drugs for supplementing and/or enhancing the preventive and/ortherapeutic effect of the compound of the present invention againstimmune system diseases include, for example, immunosuppressants,steroid, disease-modifying anti-rheumatic drugs, prostaglandins,prostaglandin synthase inhibitors, phosphodiesterase inhibitors,metalloprotease inhibitors, anti-cytokine protein formulations such asanti-TNF-α formulations, anti-IL-1 formulations, and anti-IL-6formulation, cytokine inhibitors, and nonsteroidal anti-inflammatoryagents.

The other drugs for supplementing and/or enhancing the preventive and/ortherapeutic effect of the compound of the present invention againstcirculatory system diseases include antiplatelet drugs, angiotensin IIantagonistic drugs, angiotensin-converting enzyme inhibitors, HMG-CoAreductase inhibitors, and thiazolidine derivatives.

Examples of the alkylating agents include nitrogen mustard N-oxidehydrochloride, cyclophosphamide, ifosfamide, melphalan, thiotepa,carboquone, busulfan, nimustine hydrochloride, dacarbazine, ranimustine,carmustine, chlorambucil, bendamustine, and mechlorethamine.

Examples of the antimetabolites include methotrexate, mercaptopurine,6-mercaptopurine riboside, fluorouracil, tegafur, tegafur uracil,carmofur, doxifluridine, cytarabine, enocitabine, tegafur gimestatotastat potassium, gemcitabine hydrochloride, cytarabine ocfosfate,procarbazine hydrochloride, and hydroxycarbamide.

Examples of the anticancer antibiotics include actinomycin D, mitomycinC, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicinhydrochloride, neocarzinostatin, pirarubicin hydrochloride, epirubicin(hydrochloride), idarubicin hydrochloride, chromomycin A3, bleomycin(hydrochloride), peplomycin sulfate, therarubicin, zinostatinstimalamer, gemtuzumab ozogamicin, and the like.

Examples of the plant formulations include vinblastine sulfate,vincristine sulfate, vindesine sulfate, irinotecan hydrochloride,etoposide, flutamide, vinorelbine tartrate, docetaxel hydrate,paclitaxel, and the like.

Examples of the hormones include estramustine phosphate sodium,mepitiostane, epitiostanol, goserelin acetate, fosfestrol(diethylstilbestrol phosphate), tamoxifen citrate, toremifene citrate,fadrozole hydrochloride hydrate, medroxyprogesterone acetate,bicalutamide, leuprorelin acetate, anastrozole, aminoglutethimide,androgen bicalutamide, fulvestrant, and the like.

Examples of the platinum compounds include carboplatin, cisplatin,nedaplatin, and oxaliplatin, and the like.

Examples of the anti-CD20 antibodies include rituximab, ibritumomab,ibritumomab tiuxetan, and ocrelizumab.

Examples of the anti-CD52 antibodies include alemtuzumab.

Examples of the anti-PD-1 antibodies include nivolumab, andpembrolizumab.

Examples of the G-CSF formulation include pegfilgrastim, filgrastim,lenograstim, and nartograstim.

Examples of the differentiation-inducing agent for acute promyelocyticleukemia include tamibarotene, tretinoin, and arsenic trioxideformulations.

Examples of the kinase inhibitors include EGFR inhibitors includingerlotinib hydrochloride, gefitinib, cetuximab, and panitumumab; HER2inhibitors including lapatinib and trastuzumab; BCR-ABL inhibitorsincluding imatinib, dasatinib, and nilotinib; multikinase inhibitorsincluding sunitinib, vandetanib, crizotinib, and sorafenib.

Examples of the topoisomerase inhibitor include topotecan, teniposide,irinotecan, and sobuzoxane.

Examples of the aromatase inhibitor include exemestane.

Examples of the other anticancer agents include L-asparaginase,octreotide acetate, porfimer sodium, mitoxantrone acetate, aceglatone,ubenimex, eribulin mesilate, cladribine, krestin, bexarotene, denileukindiftitox, temozolomide, nelarabine, fludarabine, bevacizumab,pemetrexed, pentostatin, bortezomib, lenalidomide, and calcium folinate.

Examples of the immunosuppressant include azathioprine, ascomycin,everolimus, salazosulfapyridine, cyclosporine, cyclophosphamide,sirolimus, tacrolimus, bucillamine, methotrexate, and leflunomide.

Examples of the steroid include amcinonide, hydrocortisone sodiumsuccinate, prednisolone sodium succinate, methylprednisolone sodiumsuccinate, ciclesonide, difluprednate, betamethasone propionate,dexamethasone, deflazacort, triamcinolone, triamcinolone acetonide,halcinonide, dexamethasone palmitate, hydrocortisone, flumetasonepivalate, prednisolone butylacetate, budesonide, prasterone sulfate,mometasone furoate, fluocinonide, fluocinolone acetonide,fludroxycortide, flunisolide, prednisolone, alclometasone propionate,clobetasol propionate, dexamethasone propionate, deprodone propionate,fluticasone propionate, beclometasone propionate, betamethasone,methylprednisolone, methylprednisolone suleptanate, methylprednisolonesodium succinate, dexamethasone sodium phosphate, hydrocortisone sodiumphosphate, prednisolone sodium phosphate, diflucortolone valerate,dexamethasone valerate, betamethasone valerate, prednisolone valerateacetate, cortisone acetate, diflorasone acetate, dexamethasone acetate,triamcinolone acetate, paramethason acetate, halopredone acetate,fludrocortisone acetate, prednisolone acetate, methylprednisoloneacetate, clobetasone butyrate, hydrocortisone butyrate, hydrocortisonebutyrate propionate, and betamethasone butyrate propionate.

Examples of the angiotensin II antagonistic drug include losartan,candesartan, valsartan, irbesartan, olmesartan, telmisartan, and thelike.

Examples of the angiotensin-converting enzyme inhibitor includealacepril, imidapril hydrochloride, quinapril hydrochloride, temocaprilhydrochloride, delapril hydrochloride, benazepril hydrochloride,captopril, trandolapril, perindopril erbumine, enalapril maleate,lisinopril, and the like.

Examples of the antiplatelet drugs include dipyridamole, and dilazephydrochloride hydrate.

Examples of the anticoagulant drugs include warfarin and heparin.

Examples of the disease-modifying anti-rheumatic drugs includeD-penicillamine, actarit, auranofin, salazosulfapyridine,hydroxychloroquine, bucillamine, methotrexate, leflunomide, lobenzaritsodium, aurothioglucose, and sodium aurothiomalate.

Examples of the prostaglandins (hereinafter, abbreviated as “PG”)include PGE1 formulations (examples: alprostadil alfadex, alprostadil,and the like), PGI2 formulations (example: beraprost sodium, and thelike), PG receptor agonists, and PG receptor antagonists. Examples ofthe PG receptor include PGE receptors (EP1, EP2, EP3, and EP4), PGDreceptors (DP, and CRTH2), PGF receptors (FP), PGI2 receptors (IP), andTX receptors (TP).

Examples of the prostaglandin synthase inhibitor includesalazosulfapyridine, mesalazine, olsalazine, 4-aminosalicylic acid,JTE-522, auranofin, carprofen, diphenpyramide, flunoxaprofen,flurbiprofen, indometacin, ketoprofen, lornoxicam, loxoprofen,meloxicam, oxaprozin, parsalmide, naproxen, piroxicam, piroxicamcinnamate, zaltoprofen, and pranoprofen.

Examples of the phosphodiesterase inhibitor include rolipram,cilomilast, Bay19-8004, NIK-616, roflumilast (BY-217), cipamfylline(BRL-61063), atizoram (CP-80633), ONO-6126, SCH-351591, YM-976,V-11294A, PD-168787, D-4396, and IC-485.

Examples of the anti-TNF-α formulation include anti-TNF-α antibodies,soluble TNF-α receptor, anti-TNF-α receptor antibodies, and solubleTNF-α binding protein, and particularly infliximab and etanercept.

Examples of the anti-IL-1 formulation include anti-IL-1 antibodies,soluble IL-1 receptor, anti-IL-1Ra antibodies and/or anti-IL-1 receptorantibodies and particularly anakinra.

Examples of the anti-IL-6 formulation include anti-IL-1 antibodies,soluble IL-6 receptor, and anti-IL-6 receptor antibodies, andparticularly tocilizumab.

Examples of the cytokine inhibitor include suplatast tosylate, T-614,SR-31747, and sonatimod.

Examples of the HMG-CoA reductase inhibitor include atorvastatin,fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, andsimvastatin.

Examples of the thiazolidine derivative include pioglitazone,ciglitazone, rosiglitazone, and troglitazone.

Furthermore, the combination drugs to be combined with a compound of thepresent invention includes not only ones discovered to date, but alsoones that may be discovered in the future.

The compound of the present invention is usually administeredsystemically or locally, by oral or parenteral administration. Examplesof oral agents include liquid medicines for internal use (for example,elixirs, syrups, pharmaceutically acceptable water-based agents,suspensions, and emulsions), and solid medicine for internal use (forexample, tablets (including sublingual tablets and orally disintegratingtablets), pills, capsules (including hard capsules, soft capsules,gelatin capsules, and microcapsules), powders, granules, and lozenges).Examples of parenteral agents include liquid medicines (for example,injection agents (subcutaneous injection agents, intravenous injectionagents, intramuscular injection agents, intraperitoneal injectionagents, and drip agents, and the like), eye drops (for example, aqueouseye drops (aqueous eye drops, aqueous eye drop suspensions, viscous eyedrops, and solubilized eye drops, etc.), and nonaqueous eye drops (forexample, nonaqueous eye drops and nonaqueous eye drop suspensions), andthe like), agents for external use (for example, ointments (ophthalmicointments, and the like)), and ear drops, and the like. Theseformulations may be controlled release agents such as rapid releaseformulations, sustained release formulations, and the like. Theseformulations can be produced by well-known methods, for example, by themethods described in The Japanese Pharmacopoeia.

Liquid medicines for internal use as the oral agent can be produced by,for example, dissolving or suspending an active ingredient in agenerally used diluent (for example, purified water, ethanol, or mixtureliquid thereof, or the like). The liquid medicine may include a wettingagent, a suspension agent, a sweetening agent, a flavoring material, anaromatic substance, a preservative, a buffer agent, and the like.

Solid medicines for internal use as the oral agent are formulated by,for example, mixing the active ingredient with, for example, a vehicle(for example, lactose, mannitol, glucose, microcrystalline cellulose,starch, and the like), a binder (for example, hydroxypropyl cellulose,polyvinylpyrrolidone, magnesium metasilicate aluminate, and the like), adisintegrant (for example, sodium carboxymethylcellulose, and the like),a lubricant (for example, magnesium stearate, and the like), astabilizer, a dissolution adjuvant (for example, glutamic acid, asparticacid, and the like), and the like, and formulating according to standardmethods. As necessary, coating may be carried out with a coating agent(for example, sugar, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, and the like), and coating of two or morelayers may be employed.

Agents for external use as parenteral agents are produced by well-knownmethods or generally used prescriptions. For example, an ointment may beproduced by incorporation or melting of an active ingredient into basematerial. The ointment base material is selected from well-knownmaterial or generally used material. For example, a single material or amixture of two or more of materials are selected from higher fatty acidsand higher fatty acid esters (for example, adipic acid, myristic acid,palmitic acid, stearic acid, oleic acid, adipate esters, myristateesters, palmitate esters, stearate esters, oleate esters, and the like),waxes (for example, beeswax, spermaceti, ceresin, and the like),surfactants (for example, polyoxyethylene alkyl ether phosphate esters,and the like), higher alcohols (for example, cetanol, stearyl alcohol,etostearyl alcohol, and the like), silicone oils (for example,dimethylpolysiloxane, and the like), hydrocarbons (for example,hydrophilic petrolatum, white petrolatum, purified lanolin, liquidparaffin, and the like), glycols (for example, ethylene glycol,diethylene glycol, propylene glycol, polyethylene glycol, macrogol, andthe like), plant oils (for example, castor oil, olive oil, sesame oil,turpentine oil, and the like), animal oils (for example, mink oil, eggyolk oil, squalane, squalene, and the like), water, absorptionpromoters, and anti-irritants. Furthermore, a humectant, preservative,stabilizer, antioxidant, fragrance, and the like, may be included.

The injection agents as parenteral agents include solutions,suspensions, emulsions and solid injection agents to be dissolved orsuspended in a solvent before use. The injection agent is used by, forexample, dissolving, suspending or emulsifying an active ingredient in asolvent. Examples of the solvent include distilled water for injection,physiological saline, vegetable oils, alcohols such as propylene glycol,polyethylene glycol, ethanol, and mixtures thereof. Furthermore, theinjection agent may contain a stabilizer, a dissolution aid (glutamicacid, aspartic acid, and Polysorbate 80 (registered trademark), etc.), asuspending agent, an emulsifying agent, a soothing agent, a buffer, apreservative, and the like. Such an injection agent is produced bysterilizing at the final step or employing an aseptic process.Furthermore, it is also possible to employ an aseptic solid product suchas a freeze-dried product produced and sterilized or dissolved inaseptic distilled water for injection or other solvent before use.

When the compound of the present invention or combination agents of thecompound of the present invention and other agents are used for theabove-mentioned purposes, they are usually administered systemically orlocally, usually by oral or parenteral administration. The doses to beadministered are different depending upon ages, body weights, symptoms,therapeutic effects, administration method, treatment time, and thelike. The doses per adult person are generally from 1 ng to 1000 mg perdose, once or several times per day, by oral administration, from 0.1 ngto 100 mg per dose, once or several times per day, by parenteraladministration, or continuous administration 1 to 24 hours per dayintravenously. Needless to say, as mentioned above, the doses to be usedvary dependent upon various conditions. Therefore, doses lower than theranges specified above may be sufficient in some cases, and doses higherthan the ranges specified above are needed in some cases.

EXAMPLES

Hereinafter, the present invention is described in detail with referenceto Examples mentioned below, but the present invention is not limitedthereto.

Solvents given in parentheses shown in chromatographic separation andTLC each indicate the eluting solvent or the developing solvent used,and the ratio is expressed in ratio by volume. The description “NHsilica” denotes that CHROMATOREX NH TLC PLATE (catalog No.; 3800003)manufactured by FUJI SILYSIA CHEMICAL LTD. is used; and “DNH silica”denotes that CHROMATOREX NH TLC PLATE (catalog No.; 3800403)manufactured by FUJI SILYSIA CHEMICAL LTD. is used;

LC-MS/ELSD was carried out in the following conditions:

{Column: Waters ACQUITY C₁₈ (particle diameter: 1.7×10⁻⁶; column length:30×2.1 mm I.D.); flow rate: 1.0 mL/min; column temperature: 40° C.;mobile phase (A): 0.1% formic acid aqueous solution; mobile phase (B):0.1% formic acid-acetonitrile solution; gradient (rate of mobile phase(A): mobile phase (B)): [0 min]95:5; [0.1 min]95:5; [1.2 min]5:95; [1.4min]5:95; [1.41 min]95:5; [1.5 min]95:5; detector: UV (PDA), ELSD, MS}

The description in a parenthesis in the NMR data shows a solvent usedfor measurement.

Name of the compounds used in this specification are named by usingACD/Name (registered trademark) manufactured by Advanced ChemistryDevelopment Inc., which is a computer program for naming compoundsaccording to the regulation of IUPAC, or named according to the namingmethod of IUPAC.

Example 1 4-[(6-chloro-3-pyridinyl)oxy]-6,7-dimethoxy quinoline

Under the stream of nitrogen, a solution of 4-chloro-6,7-dimethoxyquinoline (1.00 g) (CAS registration No.: 35654-56-9) in chlorobenzene(9 mL), 6-chloropyridine-3-ol (0.65 g), and triethyl amine (11.3 mL)were placed in a 100-mL four-necked flask, and the mixture was stirredat a bath temperature (140° C.) for five days. The resulting solutionwas left to cool to room temperature, water and ethyl acetate were addedthereto, and the solution was separated. The water layer was extractedagain with ethyl acetate, and the combined organic layer was washed witha saturated saline solution, and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure. The resultingresidue was purified by silica gel column chromatography (hexane:ethylacetate=1:8) to obtain the title compound (1.16 g) having the followingphysical property values.

TLC: Rf 0.22 (hexane:ethyl acetate=1:3);

¹H-NMR (DMSO-d₆)L δ 8.52, 8.48, 7.87-7.85, 7.66, 7.49, 7.43, 6.65, 3.95,3.93.

Example 2 5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinamine

Under the stream of nitrogen, a solution of the compound (1.15 g)produced in Example 1 in tetrahydrofuran (THF) (18 mL), 1.0 mol/Llithium bis(trimethylsilyl)amide (LHDMS) (5.45 mL),tris(dibenzylideneacetone)dipalladium(0) chloroform complex (0.19 g),and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.15 g) were placedin a 200-mL four-necked flask, and the mixture was stirred at a bathtemperature (80° C.) for 16.5 hours. Furthermore, 6 mol/L hydrochloricacid (10 mL) was added thereto, and the mixture was stirred at a bathtemperature (80° C.) for two hours. The mixture was left to cool to roomtemperature, then a sodium hydrogen bicarbonate aqueous solution andethyl acetate were added, and the resulting solution was separated. Thewater layer was extracted again with ethyl acetate, and the combinedorganic layer was washed with a saturated saline solution, and thendried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (ethyl acetate→ethyl acetate:methanol=9:1) toobtain the title compound (0.80 g) having the following physicalproperty values.

TLC: Rf 0.51 (ethyl acetate:methanol=4:1);

¹H-NMR (DMSO-d₆): δ 8.45, 7.89, 7.51, 7.38-7.36, 6.56, 6.42, 6.05, 3.94.

Example 3 ethyl 2,5-dioxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylate

1,3-cyclohexanedione (CAS registration No.: 504-02-9) (13.25 g) wasdissolved in N,N-dimethyl formamide (DMF) (200 mL) at room temperature,and tert-butoxy potassium (13.26 g) and ethyl(E)-2-cyano-3-ethoxy-2-propenoate (CAS registration No.: 94-05-3) (20.00g) were added thereto. The mixture was stirred for 21 hours. Thereaction solution was diluted with ethyl acetate, 2 mol/L hydrochloricacid aqueous solution was added thereto, and the mixture was stirred.Ethyl acetate and water were further added, and the organic layer wasextracted. The extract was washed with a saturated saline solution, thendried over anhydrous sodium sulfate, and the solvent was distilled offunder reduced pressure to obtain the title compound (23.62 g) having thefollowing physical property values.

TLC: Rf 0.35 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 1.37, 2.19, 2.61, 2.92, 4.36, 8.63.

Example 4 2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxylic acid

The compound (10.00 g) produced in Example 3 was dissolved in ethanol(200 mL) at room temperature, aniline (3.94 g) was added thereto, andthe mixture was stirred for six hours. Solids precipitated from thereaction solution were collected by filtration through Kiriyama funnel,and washed with ethanol. The obtained residue was dried under reducedpressure at 60° C. The title compound (4.01 g) having the followingphysical property values was obtained.

TLC: Rf 0.37 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 2.11, 2.60, 7.25, 7.63, 9.21.

Example 5N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The compound (105 mg) produced in Example 4 andO-(7-aza-1-benzotriazolyl)-N,N,N′,N′-tetramethyl uroniumhexafluorophosphate (HATU) (192 mg) were dissolved in DMF (2 mL) at roomtemperature, diisopropylethylamine (DIPEA) (0.17 mL) and the compound(100 mg) produced in Example 2 were added thereto, and the mixture wasstirred for 21 hours. The solvent was distilled off under reducedpressure. The resulting residue was purified by silica gelchromatography (hexane:ethyl acetate=30:70-0:100-ethylacetate:methanol=70:30) to obtain the title compound (116 mg) having thefollowing physical property values.

TLC: Rf 0.76 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 2.13, 2.60, 4.05, 6.44, 7.25, 7.42, 7.53, 7.63, 8.22,8.48, 8.51, 9.32, 11.93.

Examples 5(1) to 5(54)

The following Example compounds were obtained by the procedure havingthe same purpose as in Example 5 using the compound produced in Example2 and corresponding carboxylic acid derivatives in place of the compoundproduced in Example 4.

Example 5(1)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-7,7-dimethyl-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.75 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 1.06, 2.43, 2.48, 4.05, 6.45, 7.25, 7.43, 7.54,7.55-7.65, 8.22, 8.48, 8.51, 9.32, 11.92.

Example 5(2)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2′,5′-dioxo-1′-phenyl-2′,5′,6′,8′-tetrahydro-1′H-spiro[cyclopropane-1,7′-quinoline]-3′-carboxamide

TLC: Rf 0.69 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 0.39, 0.54, 2.41, 2.48, 4.05, 6.45, 7.22, 7.43, 7.53,7.55-7.62, 8.22, 8.49, 8.51, 9.36, 11.92.

(Byproduct)

-   N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-8′-hydroxy-2′,5′-dioxo-1′-phenyl-2′,5′,6′,8′-tetrahydro-1′H-spiro[cyclopropane-1,7′-quinoline]-3′-carboxamide

TLC: Rf 0.68 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 0.44, 0.61, 1.89, 3.39, 3.45, 4.10, 4.14, 6.76, 7.19,7.47, 7.58-7.65, 7.86, 8.25, 8.63, 9.27, 12.05.

Example 5(3)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-ethyl-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.70 min);

¹H-NMR (CDCl₃): δ 1.41-1.46, 2.25-2.29, 2.62-2.65, 3.07-3.11, 4.06,4.26-4.30, 6.45-6.47, 7.43, 7.55, 7.55-7.60, 8.29-8.31, 8.50-8.53, 9.21,12.23.

Example 5(4)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(4-fluorobenzyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.80 min);

¹H-NMR (CDCl₃): δ 2.14-2.20, 2.58-2.63, 2.96-3.01, 4.06, 5.50,6.45-6.47, 6.89-7.10, 7.26-7.37, 7.43, 7.55, 7.57-7.61, 8.29-8.30,8.50-8.54, 9.29, 12.10.

Example 5(5)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.67 min);

¹H-NMR (CDCl₃): δ 2.20-2.30, 2.60-2.64, 3.00-3.30, 3.45-3.55, 4.06,4.15-4.20, 4.40-4.60, 6.45-6.47, 7.44, 7.55-7.61, 8.30-8.31, 8.49-8.52,9.20, 12.17.

Example 5(6)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2,2-dimethylpropyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.54 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 0.99, 2.09, 2.56, 3.19, 3.94, 4.25, 6.54, 7.40, 7.53,7.86, 8.39, 8.48, 8.89, 12.19.

Example 5(7)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.59 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 2.13, 2.60, 4.05, 6.44, 7.24-7.35, 7.43, 7.54, 7.57,8.23, 8.50, 9.32, 11.88.

Example 5(8)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-6,6-dimethyl-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.51 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 1.13, 1.80-1.90, 2.40-2.60, 3.92, 3.94, 6.53-6.55,7.40, 7.50-7.53, 7.57-7.66, 7.84-7.88, 8.34-8.36, 8.40-8.43, 8.47-8.49,8.99, 11.98.

Example 5(9)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-isobutyl-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.50 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 0.94, 2.05-2.25, 2.49-2.65, 3.15-3.24, 3.93, 4.13,6.54, 7.04, 7.53, 7.86, 8.38-8.45, 8.48, 8.89, 12.24.

Example 5(10)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[(2R)-1-hydroxy-3-methyl-2-butanyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.20 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 0.70, 1.11, 2.13, 2.41, 2.87-2.99, 3.35, 4.02, 4.07,4.19, 4.88, 6.17, 7.19, 7.53, 7.86, 8.17, 8.37, 8.58, 8.61, 12.18.

Example 5(11)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[(2S)-1-hydroxy-3-methyl-2-butanyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.20 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 0.70, 1.11, 2.13, 2.41, 2.87-2.99, 3.35, 4.02, 4.07,4.19, 4.88, 6.17, 7.19, 7.53, 7.86, 8.17, 8.37, 8.58, 8.61, 12.18.

Example 5(12)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(3-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.56 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 2.13, 2.60, 4.05, 6.44, 7.07, 7.32, 7.43, 7.54, 7.59,8.23, 8.49, 9.32, 11.85.

Example 5(13)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[1-(hydroxymethyl)cyclobutyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.15 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.81-1.95, 2.16-2.29, 2.40-2.75, 2.83-3.01, 3.45,4.05, 4.06, 4.18, 4.48, 6.41, 7.39, 7.55, 7.61, 8.28, 8.46, 8.54, 9.08,11.99.

Example 5(14)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[(1R)-1-(4-fluorophenyl)ethyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.51 (ethyl acetate);

¹H-NMR (CDCl₃): δ 2.00-2.20, 2.45-3.07, 4.05, 4.06, 6.45, 7.03-7.12,7.18-7.23, 7.43, 7.55, 7.58, 8.28, 8.50, 8.51, 9.23, 12.07.

Example 5(15)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[(1S)-1-(4-fluorophenyl)ethyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.50 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 2.00-2.20, 2.45-3.07, 4.05, 4.06, 6.45, 7.03-7.12,7.18-7.23, 7.43, 7.55, 7.58, 8.28, 8.50, 8.51, 9.23, 12.07.

Example 5(16)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.52 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 2.15, 2.63, 4.05, 6.44, 7.26-7.61, 8.22, 8.49, 9.33,11.85.

Example 5(17)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2′,5′-dioxo-1′-phenyl-2′,5′,6′,8′-tetrahydro-1′H-spiro[cyclobutane-1,7′-quinoline]-3′-carboxamide

TLC: Rf 0.71 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 1.78-1.93, 2.64, 2.73, 2.93, 3.02, 4.05, 6.45, 7.24,7.42, 7.53-7.67, 8.22, 8.49, 9.29, 11.92.

Example 5(18)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-[(1S)-1-phenylethyl]-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.69 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 2.01, 2.55, 2.95, 4.05, 4.06, 6.44, 7.19, 7.29-7.43,7.55, 7.57, 8.28, 8.49-8.53, 9.25, 12.13.

Example 5(19)1-cyclopropyl-N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.69 min);

MASS (ESI, Pos.): 527 (M+H)⁺.

Example 5(20)1-(1-cyclopropyl-2-hydroxyethyl)-N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.71 min);

MASS (ESI, Pos.): 571 (M+H)⁺.

Example 5(21)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[2-(methylsulfonyl)-1-phenylethyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.67 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 2.20-2.80, 3.14, 3.92, 3.93, 4.61, 6.29, 6.49, 7.33,7.39, 7.50, 7.83, 8.34, 8.45, 8.92, 11.80.

Example 5(22)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-(3-pentanyl)-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.80 min);

MASS (ESI, Pos.): 557 (M+H)⁺.

Example 5(23)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2-hydroxy-2-methylpropyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.66 min);

MASS (ESI, Pos.): 559 (M+H)⁺.

Example 5(24)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(1-hydroxy-3-methyl-2-butanyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.71 min);

MASS (ESI, Pos.): 573 (M+H)⁺.

Example 5(25)1-cyclobutyl-N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.74 min);

MASS (ESI, Pos.): 541 (M+H)⁺.

Example 5(26)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[1-(4-fluorophenyl)ethyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.80 min);

MASS (ESI, Pos.): 609 (M+H)⁺.

Example 5(27)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-(3-pyridinyl)-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.63 min);

MASS (ESI, Pos.): 564 (M+H)⁺.

Example 5(28)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[2-(dimethylamino)ethyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.51 min);

MASS (ESI, Pos.): 558 (M+H)⁺.

Example 5(29)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2-methoxy-2-methylpropyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.65 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.19-1.35, 2.18, 2.62, 2.81, 3.16, 3.83, 4.06, 4.07,4.99, 6.45, 7.27, 7.44, 7.56, 7.59, 8.31, 8.51, 8.54, 9.23, 12.24.

Example 5(30)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(3-hydroxy-3-methyl-2-butanyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.70 min);

MASS (ESI, Pos.): 573 (M+H)⁺.

Example 5(31)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(3-oxetanyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.68 min);

MASS (ESI, Pos.): 543 (M+H)⁺.

Example 5(32)1-(4,4-difluorocyclohexyl)-N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.80 min);

MASS (ESI, Pos.): 605 (M+H)⁺.

Example 5(33)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.63 min);

MASS (ESI, Pos.): 567 (M+H)⁺.

Example 5(34)1-(cyclopropylmethyl)-N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.75 min);

MASS (ESI, Pos.): 541 (M+H)⁺.

Example 5(35)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(3-methyl-2-butanyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.82 min);

MASS (ESI, Pos.): 557 (M+H)⁺.

Example 5(36)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-hexyl-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.88 min);

MASS (ESI, Pos.): 571 (M+H)⁺.

Example 5(37)1-[(1S)-1-cyclohexylethyl]-N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.92 min);

MASS (ESI, Pos.): 597 (M+H)⁺.

Example 5(38)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-(3-phenylpropyl)-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.85 min);

MASS (ESI, Pos.): 605 (M+H)⁺.

Example 5(39)1-[(1S)-1-cyclopropylethyl]-N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.79 min);

MASS (ESI, Pos.): 555 (M+H)⁺.

Example 5(40)1-[(1R)-1-cyclopropylethyl]-N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.80 min);

MASS (ESI, Pos.): 555 (M+H)⁺.

Example 5(41)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(4-methylphenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.66 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 2.10, 2.48, 2.60, 4.05, 6.44, 7.13, 7.42, 7.53, 7.56,8.21, 8.49, 8.50, 9.31, 11.94.

Example 5(42)1-(4-chlorophenyl)-N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.60 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 2.13, 2.60, 4.05, 6.45, 7.22, 7.42, 7.53, 7.57, 7.61,8.23, 8.48, 8.50, 9.31, 11.85.

Example 5(43)1-(2,4-difluorophenyl)-N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.33 (ethyl acetate);

¹H-NMR (CDCl₃): δ 2.17, 2.62, 4.06, 6.44, 7.14, 7.31, 7.43, 7.54, 7.57,8.24, 8.50, 9.33, 11.79.

Example 5(44)1-(2-chlorophenyl)-N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.29 (ethyl acetate);

¹H-NMR (CDCl₃): δ 2.14, 2.54, 2.64, 4.05, 6.44, 7.34, 7.43, 7.55, 7.57,7.69, 8.23, 8.49, 8.51, 9.35, 11.85.

Example 5(45)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2-methylphenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.36 (ethyl acetate);

¹H-NMR (CDCl₃): δ 2.08-2.15, 2.36, 2.58-2.65, 4.05, 6.44, 7.15,7.43-7.59, 8.23, 8.48-8.52, 9.35, 11.97.

Example 5(46)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[(1R)-2-hydroxy-1-phenylethyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.15 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 2.14, 2.48, 3.04, 3.30, 4.04, 4.05, 4.51, 5.11, 6.22,7.19-7.42, 7.53, 7.73, 8.16, 8.40, 8.51, 8.86, 11.89.

Example 5(47)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[(1S)-2-hydroxy-1-phenylethyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.51 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 2.08-2.25, 2.30-2.70, 2.97-3.16, 3.16-3.40, 4.05,4.06, 4.45-4.60, 4.88-5.19, 5.67-6.15, 6.26, 7.16-7.42, 7.53, 7.72,8.18, 8.43, 8.52, 8.94, 11.90.

Example 5(48)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-[(1R)-1-phenylethyl]-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.51 (ethyl acetate);

¹H-NMR (CDCl₃): δ 1.99-2.10, 2.40-2.70, 2.91, 4.06, 6.45, 7.21,7.30-7.43, 7.55, 7.58, 8.29, 8.52, 9.26, 12.14.

Example 5(49)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[(2S)-3-methyl-2-butanyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.51 (ethyl acetate:methanol=10:1)

¹H-NMR (CDCl₃): δ 0.74, 1.07, 1.70, 2.10-2.40, 2.48-2.73, 2.95-3.15,3.96, 4.06, 4.07, 6.45, 7.43, 7.52-7.64, 8.31, 8.47-8.56, 9.21, 12.27.

Example 5(50)1-(3-chlorophenyl)-N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.72 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.98-2.07, 2.48-2.60, 3.93, 6.54, 7.40, 7.45-7.51,7.67-7.69, 7.90, 8.36, 8.41, 8.48, 8.97, 11.89.

Example 5(51)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(3-methylphenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.38 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.89-2.04, 2.36-2.62, 3.92-3.94, 6.54, 7.10-7.56,7.86, 8.35, 8.42, 8.47-8.49, 8.97, 11.97.

Example 5(52)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[(2R)-3-methyl-2-butanyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.48 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 0.74, 1.07, 1.70, 2.10-2.38, 2.49-2.75, 2.93-3.15,3.88-4.02, 4.06, 4.07, 6.45, 7.43, 7.52-7.63, 8.31, 8.46-8.58, 9.21,12.27.

Example 5(53)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-yl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.15 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.27, 2.14, 2.59, 2.73, 3.20, 4.05, 4.18, 6.44, 7.43,7.53, 7.54, 7.70, 8.24, 8.49, 8.51, 9.28, 11.88.

Example 5(54)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-2,5,6,7,8,9-hexahydro-1H-cyclohepta[b]piperidine-3-carboxamide

TLC: Rf 0.32 (ethyl acetate);

¹H-NMR (CDCl₃): δ 1.80, 1.91, 2.71, 2.77, 4.05, 6.45, 7.25, 7.43,7.53-7.66, 8.21, 8.48, 8.50, 9.11, 11.99.

Example 61-(4-fluorophenyl)-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example1→Example 2→Example 3→Example 4→Example 5, using 4-chloro-7-methoxyquinoline (CAS registration No.: 68500-37-8) in place of4-chloro-6,7-dimethoxy quinoline.

TLC: Rf 0.73 (ethyl acetate:methanol=19:1);

¹H-NMR (CDCl₃): δ 1.92-2.09, 2.40-2.70, 3.93, 6.54, 7.29, 7.41-7.60,7.87, 8.21, 8.36, 8.41, 8.61, 8.97, 11.94.

Example 6(1) to 6(38)

The following Example compounds were obtained by the procedure havingthe same purpose as in Example 6, using 4-chloro-7-methoxy quinoline ora corresponding quinoline derivative in place of it and the compoundproduced in Example 4 or a corresponding carboxylic acid derivative inplace of it.

Example 6(1)N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.30 (ethyl acetate, NH silica);

¹H-NMR (DMSO-d₆): δ 1.98, 2.45-2.57, 3.92, 6.52, 7.28, 7.40, 7.44, 7.46,7.57-7.67, 7.85, 8.20, 8.35, 8.40, 8.60, 8.97, 11.95.

Example 6(2)N-{5-[(6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.77 min);

¹H-NMR (CDCl₃): δ 2.05-2.20, 2.51-2.68, 3.97, 6.52, 7.25-7.26,7.27-7.29, 7.41, 7.54-7.67, 8.00, 8.22, 8.50, 8.55, 9.33, 11.93.

Example 6(3)1-[(2S)-1-hydroxy-3-methyl-2-butanyl]-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.71 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 0.72, 1.12, 2.18, 2.48, 2.92-3.02, 3.31, 3.95, 4.04,4.17, 4.77, 5.23, 6.23, 7.21, 7.78, 8.21, 8.24, 8.51, 8.55, 8.77, 12.16.

Example 6(4)1-[(2R)-1-hydroxy-3-methyl-2-butanyl]-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.71 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 0.72, 1.12, 2.18, 2.48, 2.92-3.02, 3.31, 3.95, 4.04,4.17, 4.77, 5.23, 6.23, 7.21, 7.78, 8.21, 8.24, 8.51, 8.55, 8.77, 12.16.

Example 6(5)1-(3-fluorophenyl)-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.43 (ethyl acetate:methanol=19:1);

¹H-NMR (CDCl₃): δ 1.93-2.08, 2.40-2.65, 3.93, 6.54, 7.27-7.55,7.65-7.76, 7.87, 8.21, 8.34-8.47, 8.62, 8.98, 11.91.

Example 6(6)2,5-dioxo-1-phenyl-N-(5-{[7-(trifluoromethyl)-4-quinolinyl]oxy}-2-pyridinyl)-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 1.06 min);

¹H-NMR (DMSO-d₆): δ 2.00, 2.52-2.55, 6.88, 7.46-7.48, 7.58-7.66,7.93-7.96, 8.40-8.44, 8.46, 8.57, 8.85, 8.99, 11.99.

Example 6(7)1-cyclobutyl-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.69 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.70-1.90, 1.95-2.10, 2.35-2.60, 2.73-2.89,3.04-3.15, 3.94, 4.89-5.03, 6.55, 7.30, 7.42, 7.88, 8.22, 8.40, 8.42,8.62, 8.83, 12.16.

Example 6(8)1-(2,2-dimethylpropyl)-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.65 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 0.99, 2.00-2.16, 2.48-2.65, 3.15-3.22, 3.94,4.12-4.38, 6.55, 7.30, 7.42, 7.88, 8.22, 8.39, 8.42, 8.62, 8.90, 12.20.

Example 6(9)N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-6,6-dimethyl-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.55 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.13, 1.80-1.90, 2.34-2.56, 3.92, 6.54, 7.29, 7.41,7.48-7.68, 7.87, 8.20, 8.35, 8.41, 8.61, 8.99, 11.98.

Example 6(10)1-(4-chlorophenyl)-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.52 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.91-2.04, 2.37-2.60, 3.93, 6.54, 7.29, 7.41, 7.52,7.72, 7.88, 8.20, 8.34, 8.41, 8.61, 8.97, 11.91.

Example 6(11)N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(4-methylphenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.41 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.91-2.03, 2.42, 2.40-2.60, 3.93, 6.54, 7.26-7.46,7.87, 8.20, 8.36, 8.41, 8.61, 8.96, 11.97.

Example 6(12)1-(4,4-difluorocyclohexyl)-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.50 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.81, 2.25, 2.31, 2.62, 3.08, 3.30, 3.98, 4.10, 6.43,7.25, 7.42, 7.57, 8.24, 8.30, 8.51, 8.61, 9.19, 12.08.

Example 6(13)1-(cyclopropylmethyl)-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.55 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 0.62, 1.15, 2.26, 2.64, 3.15, 3.98, 4.20, 6.43, 7.23,7.42, 7.57, 8.23, 8.29, 8.51, 8.61, 9.22, 12.23.

Example 6(14)1-[(1R)-1-cyclopropylethyl]-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.55 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 0.06, 0.30, 0.56, 0.77, 1.80, 2.24, 2.60, 2.89, 3.43,3.98, 6.44, 7.22, 7.43, 7.56, 8.23, 8.30, 8.51, 8.61, 9.20, 12.29.

Example 6(15)1-[(1S)-1-cyclopropylethyl]-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.55 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 0.06, 0.30, 0.56, 0.77, 1.80, 2.24, 2.60, 2.89, 3.43,3.98, 6.44, 7.22, 7.43, 7.56, 8.23, 8.30, 8.51, 8.61, 9.20, 12.29.

Example 6(16)1-(4-fluorophenyl)-N-{5-[(6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.69 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 2.13, 2.60, 3.97, 6.52, 7.29-7.35, 7.41, 7.55-7.60,8.00, 8.23, 8.49, 8.54, 9.32, 11.88.

Example 6(17)1-isobutyl-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.34 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆):δ 0.94, 2.08-2.20, 2.40-2.60, 3.12-3.26, 3.94, 4.12,6.55, 7.30, 7.42, 7.88, 8.22, 8.39, 8.41, 8.62, 8.90, 12.24.

Example 6(18)N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2′,5′-dioxo-1′-phenyl-2′,5′,6′,8′-tetrahydro-1′H-spiro[cyclobutane-1,7′-quinoline]-3′-carboxamide

TLC: Rf 0.56 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.65-1.91, 2.63-2.74, 3.93, 7.29, 7.45, 7.46-7.53,7.58-7.71, 7.87, 8.20, 8.36, 8.41, 8.61, 8.94, 11.94.

Example 6(19)1-(2,4-difluorophenyl)-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.51 (ethyl acetate);

¹H-NMR (CDCl₃): δ 2.16, 2.62, 3.97, 6.42, 7.10-7.33, 7.42, 7.56,8.21-8.24, 8.49, 8.60, 9.33, 11.79.

Example 6(20)1-(2-chlorophenyl)-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.40 (ethyl acetate);

¹H-NMR (CDCl₃): δ 2.14, 2.55, 2.63, 3.97, 6.41, 7.23, 7.35, 7.42,7.53-7.58, 7.68, 8.21, 8.23, 8.49, 8.60, 9.34, 11.84.

Example 6(21)N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2-methylphenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.44 (ethyl acetate);

¹H-NMR (CDCl₃): δ 2.15-2.20, 2.35, 2.58-2.67, 3.97, 6.41, 7.15, 7.24,7.41-7.49, 7.56, 8.21, 8.23, 8.49, 8.60, 9.34, 11.96.

Example 6(22)1-[1-(hydroxymethyl)cyclobutyl]-N-{5-[(6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.15 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.87, 2.18, 2.40, 2.62, 2.94, 3.44, 3.98, 4.10, 4.18,4.50, 6.46, 7.38, 7.58, 7.62, 7.92, 8.28, 8.49, 8.57, 9.02, 12.02.

Example 6(23)1-[1-(hydroxymethyl)cyclobutyl]-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.15 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.95, 2.21, 2.38-2.69, 2.95, 3.42, 3.68, 3.97, 4.15,4.46, 6.40, 7.23, 7.39, 7.61, 8.24, 8.28, 8.53, 8.58, 9.10, 11.99.

Example 6(24)N-{5-[(6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2-methylphenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.25 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 2.12, 2.26, 2.60, 3.97, 6.51, 7.15, 7.40-7.49, 7.58,8.00, 8.23, 8.49, 8.55, 9.34, 11.98.

Example 6(25)1-(2-chlorophenyl)-N-{5-[(6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.25 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 2.15, 2.57, 2.63, 3.97, 6.51, 7.35-7.61, 7.68, 8.00,8.23, 8.50, 8.55, 9.34, 11.86.

Example 6(26)1-(2,4-difluorophenyl)-N-{5-[(6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.25 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 2.18, 2.62, 3.97, 6.51, 7.18, 7.21-7.40, 7.41, 7.57,8.01, 8.24, 8.50, 8.55, 9.32, 11.79.

Example 6(27)1-[(1S)-1-cyclopropylethyl]-N-{5-[(6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.60 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 0.03-0.13, 0.20-0.40, 0.49-0.67, 0.69-0.89, 1.81,2.09-2.42, 2.47-2.72, 2.89, 3.31-3.52, 3.98, 6.53, 7.42, 7.55-7.64,8.00, 8.31, 8.53, 8.56, 9.21, 12.30.

Example 6(28)1-[(1S)-2-hydroxy-1-phenylethyl]-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.54 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 2.07-2.29, 2.36-2.68, 2.97-3.16, 3.17-3.43, 3.96,4.45-4.62, 4.95-5.23, 5.68-6.05, 6.22, 7.12-7.43, 7.72, 8.17, 8.23,8.47-8.56, 8.86, 11.90.

Example 6(29)1-[(1R)-1-(4-fluorophenyl)ethyl]-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.58 (ethyl acetate);

¹H-NMR (CDCl₃): δ 2.00, 2.05, 2.40-2.80, 2.96, 3.98, 6.43, 7.08,7.18-7.29, 7.42, 7.58, 8.24, 8.28, 8.51, 8.61, 9.25, 12.07.

Example 6(30)N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-[(1R)-1-phenylethyl]-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.58 (ethyl acetate);

¹H-NMR (CDCl₃): δ 1.99-2.10, 2.40-2.70, 2.90, 3.98, 6.43, 7.22,7.27-7.43, 7.59, 8.24, 8.28, 8.52, 8.61, 9.26, 12.13.

Example 6(31)1-(2-fluorophenyl)-N-{5-[(6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.60 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 2.06-2.25, 2.63, 3.97, 6.52, 7.42, 7.51-7.67, 7.99,8.23, 8.50, 8.55, 9.33, 11.85.

Example 6(32)1-(3-fluorophenyl)-N-{5-[(6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.66 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 2.04-2.26, 2.53-2.70, 3.97, 6.52, 6.99-7.14,7.27-7.36, 7.37-7.44, 7.52-7.68, 7.99, 8.23, 8.49, 8.55, 9.32, 11.85.

Example 6(33)N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[(2S)-3-methyl-2-butanyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.57 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 0.74, 1.07, 1.70, 2.10-2.34, 2.45-2.76, 2.94-3.14,3.86-3.96, 3.98, 6.42, 7.21-7.25, 7.43, 7.58, 8.24, 8.30, 8.52, 8.61,9.21, 12.27.

Example 6(34)1-(2-fluorophenyl)-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.35 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.96-2.18, 2.30-2.60, 3.93, 6.54, 7.29, 7.41,7.44-7.72, 7.88, 8.21, 8.36, 8.41, 8.61, 9.00, 11.81.

Example 6(35)N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(3-methylphenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.50 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.94-2.05, 2.40, 2.45-2.60, 3.93, 6.54, 7.22-7.55,7.87, 8.21, 8.36, 8.42, 8.62, 8.97, 11.97.

Example 6(36)1-(3-chlorophenyl)-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.74 (ethyl acetate:methanol=19:1);

¹H-NMR (DMSO-d₆): δ 1.98-2.07, 2.45-2.60, 3.93, 6.54, 7.29, 7.41,7.46-7.51, 7.66-7.69, 7.87, 8.20, 8.36, 8.41, 8.61, 8.97, 11.89.

Example 6(37)N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-[(2R)-3-methyl-2-butanyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.55 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 0.74, 1.07, 1.70, 2.12-2.38, 2.47-2.74, 2.95-3.20,3.90-3.95, 3.98, 6.43, 7.20-7.25, 7.43, 7.58, 8.24, 8.30, 8.52, 8.61,9.21, 12.26.

Example 6(38)1-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-yl]-N-{5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.15 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.28, 2.14, 2.62, 2.75, 3.10, 3.97, 4.18, 6.41, 7.22,7.42, 7.52-7.60, 7.70, 8.21, 8.23, 8.48, 8.60, 9.27, 11.87.

Example 7 tert-butylN-[5-[(6,7-dimethoxy-4-quinazolinyl)amino]-2-pyridyl]carbamate

4-chloro-6,7-dimethoxyquinazoline (CAS registration No.: 13790-39-1)(450 mg) and tert-butyl (5-aminopyridin-2-yl)carbamate (420 mg) weredissolved in N,N-dimethyl acetamide (DMA) (20 mL) at room temperature. 4mol/L hydrochloric acid-dioxane (0.5 mL) was added thereto at 50° C.,and the mixture was stirred. Thereafter, the resulting solution washeated to 80° C. and stirred for three hours. The resulting solution wasleft to cool to room temperature, methyl tert-butyl ether (MTBE) wasadded to the reaction solution, solids precipitated from the reactionsolution were collected by filtration through Kiriyama funnel, andwashed with MTBE. The resulting residue was dried under reduced pressureat 60° C. The title compound (821 mg) having the following physicalproperty values was obtained.

TLC: Rf 0.45 (ethyl acetate:methanol=5:1);

¹H-NMR (DMSO-d₆): δ 1.49, 4.00, 7.34, 7.88, 8.05, 8.32, 8.56, 8.84,10.02, 11.54.

Example 8 N⁵-(6,7-dimethoxy-4-quinazolinyl)pyridine-2,5-diamine

The compound (800 mg) produced in Example 7 was dissolved indichloromethane (10 mL) at room temperature, trifluoroacetic acid (0.3mL) was added thereto, and the mixture was stirred at room temperaturefor six hours. The reaction solution was diluted with ethyl acetate, andsaturated sodium bicarbonate water was added to the reaction solutionand stirred. Ethyl acetate and water were further added, and the organiclayer was extracted. THF and water were added to the water layer, andthe organic layer was extracted. The organic layer was collected, washedwith a saturated saline solution, dried over anhydrous sodium sulfate,and the solvent was distilled off under reduced pressure. Ethyl acetateand hexane were added to the resulting residue, followed by stirring atroom temperature. The solid was washed with ether in a slurry form. Theresidue collected by filtration through Kiriyama funnel was dried underreduced pressure at 60° C. to obtain the title compound (598 mg) havingthe following physical property values.

TLC: Rf 0.16 (ethyl acetate:methanol=5:1);

¹H-NMR (DMSO-d₆): δ 3.91, 5.83, 6.49, 7.12, 7.65, 7.82, 8.09, 8.30,9.36.

Example 9N-{5-[(6,7-dimethoxy-4-quinazolinyl)amino]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The compound produced in Example 4 (76 mg) and HATU (154 mg) weredissolved in DMF (1 mL) at room temperature. To the resulting solution,DIPEA (0.14 mL) and the compound produced in Example 8 (80 mg) wereadded, and the mixture was stirred for 18 hours. The reaction solutionwas diluted with ethyl acetate, and saturated sodium bicarbonate waterwas added and stirred. Ethyl acetate and water were further added, andthe organic layer was extracted. The organic layer was washed with asaturated saline solution, dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The resulting residuewas purified by silica gel chromatography (hexane:ethylacetate=30:70→0:100→ethyl acetate:methanol=70:30) to obtain the titlecompound (57 mg) having the following physical property values.

TLC: Rf 0.59 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 2.10, 2.58, 4.04, 7.04, 7.13, 7.25, 7.59, 8.20, 8.41,8.50, 8.64, 9.30, 11.82.

Examples 9(1) to 9(4)

The following Example compounds were obtained by the procedure havingthe same purpose as in Example 7→Example 8→Example 9, using4-chloro-6,7-dimethoxyquinazoline or a corresponding quinolinederivative in place of it, tert-butyl (5-aminopyridin-2-yl)carbamate ora corresponding amine derivative in place of it, and the compoundproduced in Example 4.

Example 9(1)N-{5-[(6,7-dimethoxy-4-quinolinyl)amino]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamidetrifluoroacetate

TLC: Rf 0.21 (dichloromethane:methanol=10:1);

¹H-NMR (DMSO-d₆): δ 1.86-2.14, 2.49-2.62, 3.98, 4.02, 6.75, 7.35-7.40,7.41-7.52, 7.53-7.73, 7.94-8.07, 8.36-8.56, 8.99, 10.42, 12.03, 14.00.

Example 9(2)

N-{4-[(6,7-dimethoxy-4-quinolinyl)amino]phenyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.75 min);

¹H-NMR (CD3 OD): δ 2.04-2.13, 2.56-2.64, 4.01, 4.02, 6.82, 7.24,7.35-7.42, 7.59-7.67, 7.69, 7.75-7.79, 8.19, 9.17.

Example 9(3)N-{5-[(7-methoxy-4-quinolinyl)amino]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.63 (ethyl acetate:methanol:ammonia water=9:1:0.5);

¹H-NMR (DMSO-d₆): δ 1.90-2.05, 2.40-2.60, 3.89, 6.70, 7.18, 7.25,7.42-7.50, 7.54-7.68, 7.86, 8.22-8.40, 8.97, 8.99, 11.85.

Example 9(4)N-{4-[(6,7-dimethoxy-4-quinazolinyl)amino]phenyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.79 min);

¹H-NMR (CD₃OD): δ 1.94-2.07, 2.50-2.58, 3.94, 3.96, 7.18, 7.43-7.51,7.57-7.68, 7.75, 7.87, 8.50, 8.95, 9.69, 11.48.

Example 105-[(E)-{[3-(benzyloxy)phenyl]imino}methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione

3-benzyloxyaniline (25 g), meldrum's acid (22 g), ethyl orthoformate (22g), and ethanol (25 mL) were placed in a 200-mL eggplant flask. Themixture was heated and refluxed for 80 min, and left to cool to roomtemperature. Then, the precipitated powder was collected by filtration.The powder was washed with ethanol (50 mL) and dried to obtain the titlecompound (43 g) having the following physical property values.

TLC: Rf 0.48 (hexane:ethyl acetate=2:1);

¹H-NMR (DMSO-d₆): δ 1.66, 5.15, 6.88, 7.11, 7.30-7.45, 8.60, 11.2.

Example 11 7-(benzyloxy)-4(1H)-quinolinone

The compound produced in Example 10 (42 g) and 1,2-dichlorobenzene (420mL) were placed in a 1 L-eggplant flask. The mixture was heated andrefluxed for 5.5 hours, and left to cool to room temperature. Then, theprecipitated powder was collected by filtration. The powder was washedwith methanol (84 mL) and dried to obtain the title compound (18 g)having the following physical property values.

TLC: Rf 0.60 (ethyl acetate:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 5.19, 5.92, 6.98, 7.32-7.43, 7.77, 7.97.

Example 12 7-(benzyloxy)-4-chloroquinolinone

Under argon atmosphere, the compound produced in Example 11 (17 g),toluene (34 mL) and phosphorus oxychloride (10 g) were placed in a300-mL eggplant flask. The mixture was heated and refluxed for 2.5hours, left to cool to 70° C., and diluted with ethyl acetate (135 mL).Thereafter, the mixture was left to cool to room temperature, and wasneutralized by 2 mol/L sodium hydroxide aqueous solution. The resultingsolution was extracted with ethyl acetate, washed with a saturatedsaline solution and dried over anhydrous sodium sulfate. Thereby, thesolvent was distilled off under reduced pressure to obtain the titlecompound (18 g) having the following physical property values.

TLC: Rf 0.60 (hexane:ethyl acetate=2:1);

¹H-NMR (CDCl₃): δ 5.22, 7.34-7.51, 8.13, 8.86.

Example 13 7-(benzyloxy)-4-[(6-chloro-3-pyridinyl)oxy]quinolinone

The compound produced in Example 12 (15 g), 6-chloropyridine-3-ol (8.3g), 4-dimethylaminopyridine (7.5 g), and toluene (75 mL) were placed ina 300-mL eggplant flask. The mixture was heated at 110° C. for 6.5hours, then left to cool to room temperature. Water and ethyl acetatewere added thereto, and the resulting solution was separated. Theextract solution was washed with a saturated saline solution, dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. Then, the resulting residue was dissolved in a smallamount of ethyl acetate, and crystallized by adding methanol to thesolution. The precipitates were then collected by filtration to obtainthe title compound (15 g) having the following physical property values.

TLC: Rf 0.37 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 5.24, 6.46, 7.31-7.52, 8.19, 8.34, 8.65.

Example 14 5-{[7-(benzyloxy)-4-quinolinyl]oxy}-2-pyridinamine

Under argon atmosphere, a solution of the compound produced in Example13 (5 g) in THF (25 mL), 1.0 mol/L LHMDS (3.5 mL),tris(dibenzylideneacetone) dipalladium(0) chloroform complex (0.63 g),and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.73 g) were placedin a 200-mL 4-diameter eggplant flask, and the mixture was stirred at70° C. Disappearance of the raw material was confirmed, the resultingproduct was left to cool to room temperature, then water and ethylacetate were added, and the solution was separated. After extractionwith ethyl acetate, the solution was washed with a saturated salinesolution, dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The resulting residue wassuspended in acetonitrile (100 mL), and 2.0 mol/L hydrochloric acid (10mL) was added to the suspension, and the mixture was stirred at roomtemperature for 2.5 hours. 1.0 mol/L sodium hydroxide aqueous solution,a saturated sodium hydrogen bicarbonate aqueous solution, and ethylacetate were added, and the solution was separated. The extractedsolution was washed with a saturated saline solution, dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=1:1→0:1) to obtain the titlecompound (2.9 g) having the following physical property values.

TLC: Rf 0.33 (dichloromethane:ethyl acetate:methanol=8:4:1);

¹H-NMR (DMSO-d₆): δ 5.29, 6.06, 6.41, 6.55, 7.31-7.52, 7.88, 8.20, 8.56.

Example 15N-(5-{[7-(benzyloxy)-4-quinolinyl]oxy}-2-pyridinyl)-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The compound produced in Example 14 (800 mg), the compound produced inExample 4 (660 mg), DIPEA (1.2 mL), and DMF (16 mL) were placed in a30-mL eggplant flask, and finally HATU (1.1 g) was added thereto,followed by stirring at room temperature overnight. After disappearanceof the raw material was confirmed, water and ethyl acetate were added,and the resulting solution was separated. The resulting solution wasextracted with ethyl acetate, and then washed with water and a saturatedsaline solution sequentially in this order, and dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure.The resulting residue was dissolved in a small amount of ethyl acetate,and crystallized by adding methanol. The precipitate was filtered toobtain the title compound (1.2 g) having the following physical propertyvalues.

TLC: Rf 0.74 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 2.11, 2.59, 5.23, 6.42, 7.25-7.63, 8.20, 8.24, 8.49,8.59, 9.32, 11.92.

Example 16N-{5-[(7-hydroxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The compound produced in Example 15 (500 mg), 20% palladiumhydroxide-carbon (250 mg), ethyl acetate (18 mL), and methanol (2 mL)were placed in a 200-mL eggplant flask. Under hydrogen atmosphere, themixture was stirred at room temperature for four hours, followed byfiltration through Celite. The filtrate was distilled off under reducedpressure to obtain the title compound (360 mg) having the followingphysical property values.

TLC: Rf 0.63 (ethyl acetate:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 2.00, 2.50, 6.44, 7.19, 7.25, 7.46, 7.60, 7.85,8.15, 8.34, 8.41, 8.53, 8.97, 10.28, 11.95.

Example 17N-[5-({7-[3-(dimethylamino)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The compound produced in Example 16 (50 mg) was dissolved in THF (1 mL)at room temperature, and 3-(dimethylamino)-1-propanol (30 mg),1,1′-azobis(N,N-dimethyl formamide) (50 mg), and tributylphosphine(0.071 mL) were added sequentially. The mixture was stirred at 60° C.for 20 hours, and the solvent was distilled off under reduced pressure.The resulting residue was purified by silica gel chromatography(hexane:ethyl acetate=30:70-0:100-ethyl acetate:methanol=70:30) toobtain the title compound (22 mg) having the following physical propertyvalues.

TLC: Rf 0.75 (ethyl acetate:methanol=5:1, NH silica);

¹H-NMR (CDCl₃): δ 2.11, 2.34, 2.59, 4.19, 6.40, 7.25, 7.40, 7.54, 7.62,8.20, 8.23, 8.49, 8.59, 9.33, 11.92.

Examples 17(1) to 17(8)

The following Example compounds were obtained by the procedure havingthe same purpose as in Example 16→Example 17, using the compoundproduced in Example 16 and corresponding alcohol derivatives in place of3-(dimethylamino)-1-propanol.

Example 17(1)N-(5-{[7-(3-hydroxy-3-methylbutoxy)-4-quinolinyl]oxy}-2-pyridinyl)-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.78 (ethyl acetate:methanol=5:1, NH silica);

¹H-NMR (CDCl₃): δ 1.35, 2.09, 2.60, 4.36, 6.41, 7.21, 7.44, 7.55,7.58-7.65, 8.21, 8.22, 8.49, 8.60, 9.32, 11.92.

Example 17(2)N-[5-({7-[3-(4-morpholinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.33 (ethyl acetate, DNH silica);

¹H-NMR (CDCl₃): δ 2.00-2.20, 2.45-2.52, 2.53-2.65, 3.72-3.75, 4.18-4.22,6.40-6.42, 7.20-7.30, 7.40-7.41, 7.53-7.70, 8.19-8.22, 8.47-8.50,8.58-8.60, 9.32, 11.92.

Example 17(3)N-[5-({7-[2-(4-morpholinyl)ethoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.80 (ethyl acetate:methanol=5:1, NH silica);

¹H-NMR (CDCl₃): δ 2.10, 2.56-2.64, 2.90, 3.76, 4.29, 6.42, 7.22-7.28,7.40, 7.53-7.65, 8.20, 8.22, 8.49, 8.60, 9.33, 11.92.

Example 17(4)1-[(2S)-1-hydroxy-3-methyl-2-butanyl]-N-[5-({7-[3-(4-morpholinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.18 (ethyl acetate, DNH silica);

¹H-NMR (CDCl₃): δ 0.73, 1.13, 1.98-2.11, 2.12-2.26, 2.38-2.63,2.82-3.08, 3.18-3.41, 3.70-3.79, 3.99-4.08, 4.09-4.27, 4.56-4.79, 6.26,7.21, 7.26-7.29, 7.74, 8.18-8.27, 8.48-8.59, 8.86, 12.15.

Example 17(5)1-(2,2-dimethylpropyl)-N-[5-({7-[3-(4-morpholinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.41 (ethyl acetate, DNH silica);

¹H-NMR (CDCl₃): δ 1.06, 2.01-2.13, 2.14-2.30, 2.44-2.52, 2.53-2.69,3.01-3.16, 3.67-3.79, 4.21, 6.42, 7.23, 7.42, 7.57, 8.23, 8.29, 8.53,8.60, 9.22, 12.18.

Example 17(6)1-(1-methyl-1H-pyrazole-4-yl)-N-[5-({7-[3-(4-morpholinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.50 (ethyl acetate:methanol=10:1, NH silica);

¹H-NMR (CDCl₃): δ 2.01-2.21, 2.46-2.52, 2.54-2.66, 2.76, 3.69-3.77,4.03, 4.20, 6.42, 7.22, 7.41, 7.52, 7.53-7.60, 8.17-8.26, 8.48, 8.59,9.28, 11.90.

Example 17(7)1-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-yl]-N-[5-({7-[3-(4-morpholinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.50 (ethyl acetate:methanol=10:1, NH silica);

¹H-NMR (CDCl₃): δ 1.28, 2.01-2.22, 2.45-2.53, 2.54-2.66, 2.69-2.80,3.20, 3.68-3.78, 4.16-4.25, 6.41, 7.19-7.25, 7.41, 7.52-7.60, 7.69,8.16-8.26, 8.49, 8.59, 9.28, 11.87.

Example 17(8)1-[(1R)-1-(4-fluorophenyl)ethyl]-N-[5-({7-[3-(4-morpholinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.62 (ethyl acetate:methanol=10:1, NH silica);

¹H-NMR (CDCl₃): δ 1.93-2.17, 2.41-2.64, 2.81-3.13, 3.74, 4.21, 6.42,7.02-7.13, 7.18-7.26, 7.42, 7.57, 8.23, 8.28, 8.51, 8.60, 9.25,11.99-12.11.

Example 18 (4-bromophenyl)(6,7-dimethoxy-4-quinazolinyl)methanone

At room temperature, 4-chloro-6,7-dimethoxyquinazoline (224 mg),4-bromobenzaldehyde (221 mg), and 1,3-dimethyl imidazolium iodide (74mg) were placed in a 50-mL eggplant flask, and the mixture was suspendedin 1,4-dioxane (3 mL). At room temperature, 60% sodium hydride (52 mg)was added and stirred. Thereafter, the mixture was heated to 100° C. andstirred for one hour. The mixture was left to cool to room temperature,the reaction solution was diluted with ethyl acetate (10 mL), and waterwas added to the solution (10 mL). The precipitated crystals werecollected by filtration to obtain the title compound (196 mg) having thefollowing physical property values.

TLC: Rf 0.31 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 3.99, 4.10, 7.42, 7.43, 7.64-7.68, 7.84-7.88, 9.23.

Example 19 2-methyl-2-propanyl{4-[(6,7-dimethoxy-4-quinazolinyl)carbonyl]phenyl}carbamate

Under argon atmosphere, the compound produced in Example 18 (149 mg),tert-butyl carbamate (51 mg),tris(dibenzylideneacetone)dipalladium-chloroform adduct (21 mg),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg), and cesiumcarbonate (182 mg) were suspended in 1,4-dioxane (4 mL) in a 50-mLeggplant flask. Thereafter, the suspension was heated to 100° C.,stirred for 12 hours, and then left to cool to room temperature. Waterwas added thereto, followed by extraction with ethyl acetate. Theextracted solution was washed with water and a saturated salinesolution, and then dried over anhydrous sodium sulfate. Thereafter, thesolvent was distilled off under reduced pressure, followed bypurification by silica gel column chromatography (hexane:ethylacetate=1:1) to obtain the title compound (145 mg) having the followingphysical property values.

TLC: Rf 0.17 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 1.53, 3.96, 4.09, 6.73, 7.33, 7.40, 7.47-7.51,7.92-7.96, 9.22.

Example 20 (4-aminophenyl) (6,7-dimethoxy-4-quinazolinyl)methanonehydrochloride

The compound produced in Example 19 (41 mg) was suspended was suspendedin methanol (0.5 mL) in a 50-mL eggplant flask at room temperature. 4mol/L hydrogen chloride/ethyl acetate solution (1 mL) was added, and thereaction mixture was stirred at room temperature for one hour, and thenconcentrated to obtain the title compound (35 mg) having the followingphysical property values.

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 3.79, 4.01, 6.57-6.60, 7.06, 7.46, 7.54-7.57, 9.14.

Example 21N-{4-[(6,7-dimethoxy-4-quinazolinyl)carbonyl]phenyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 5 usingthe compound produced in Example 20 and the compound produced in Example4.

TLC: Rf 0.55 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 2.06-2.14, 2.54-2.63, 3.95, 4.11, 7.26-7.29, 7.33,7.41, 7.61-7.70, 7.82-7.86, 7.94-7.97, 9.23, 9.32, 11.70.

Example 22 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline

4-aminophenol (500 mg) was dissolved in dimethyl sulfoxide (DMSO) (5 mL)at room temperature, and 55% sodium hydride (98 mg) was added thereto.Thereafter, 4-chloro-6,7-dimethoxy quinoline (244 mg) was added, and themixture was stirred at 100° C. for three hours. The reaction solutionwas diluted with ethyl acetate, saturated sodium bicarbonate water wasadded, and the mixture was stirred. Furthermore, ethyl acetate and waterwere added, and the organic layer was extracted. The organic layer waswashed with a saturated saline solution, and then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure.The resulting residue was washed with methanol to obtain the titlecompound (442 mg) having the following physical property values.

TLC: Rf 0.57 (ethyl acetate);

¹H-NMR (CDCl₃): δ 3.71, 4.04, 6.41, 6.76, 6.98, 7.39, 7.57, 8.44.

Example 23N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 5, usingthe compound produced in Example 22 and the compound produced in Example4.

TLC: Rf 0.72 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 2.11, 2.60, 4.05, 6.49, 7.14, 7.28, 7.43, 7.56,7.61-7.70, 7.80, 8.47, 9.34, 11.46.

Examples 23(1) to 23(3)

The following Example compounds were obtained by the procedure havingthe same purpose as in Example 22→Example 23, using4-chloro-6,7-dimethoxy quinoline or a corresponding quinoline derivativein place of it, 4-aminophenol or a corresponding phenol derivative inplace of it.

Example 23(1)2,5-dioxo-1-phenyl-N-[4-(4-quinolinyloxy)phenyl]-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.79 min);

¹H-NMR (CDCl₃): δ 2.05-2.18, 2.53-2.69, 6.56, 7.12-7.20, 7.26-7.34,7.54-7.85, 8.08, 8.36, 8.66, 9.34, 11.45.

Example 23(2)N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-methylphenyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 2.05-2.15, 2.32, 2.53-2.63, 4.04, 4.05, 6.50, 7.00,7.06, 7.26-7.30, 7.42, 7.55-7.68, 8.30, 8.48, 9.35, 11.23.

Example 23(3)N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]-2,6-difluorophenyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.28 (ethyl acetate);

¹H-NMR (CDCl₃): δ 2.06-2.14, 2.55-2.63, 4.03, 4.05, 6.69, 6.78-6.83,7.26-7.30, 7.41, 7.45, 7.56-7.68, 8.58, 9.32, 10.77.

Example 24 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxy quinoline

6,7-dimethoxy quinoline-4-ol (5.0 g), cesium carbonate (1.3 g) and1,2-difluoro-4-nitrobenzene (3.5 mL) were added into DMF (20 mL), andthe mixture was stirred at room temperature for six hours. The reactionsolution was diluted with ethyl acetate, and then the organic layer waswashed with water. The water layer was extracted with ethyl acetatetwice, and the combined organic layer was washed with a saturated salinesolution, and dried over anhydrous sodium sulfate. The organic layer wasconcentrated. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:1→0:100) to obtain the titlecompound (2.3 g) having the following physical property values.

TLC: Rf 0.62 (hexane:ethyl acetate=1:9);

¹H-NMR (CDCl₃): δ 4.04, 4.07, 6.55, 7.31-7.38, 7.45, 7.47, 8.11-8.26,8.19, 8.58.

Example 25 4-[(6,7-dimethoxy quinoline-4-yl)oxy]-3-fluoroaniline

The compound produced in Example 24 (2.1 g) was dissolved inDMF:water=3:1 (45 mL). Zinc (3.9 g) and ammonium chloride (1.9 mg) wereadded to the solution, and the solution was stirred at room temperaturefor one hour. Then the reaction solution was filtered through Celite.Saturated sodium hydrogen carbonate aqueous solution was added to thefiltrate and solid precipitate was removed by filtration through Celite.Ethyl acetate was added thereto, and the water layer was extracted withethyl acetate. The combined organic layer was washed with a saturatedsaline solution, and dried over anhydrous sodium sulfate. The organiclayer was concentrated. The title compound (1.9 g) having the followingphysical property values was obtained.

TLC: Rf 0.35 (hexane:ethyl acetate=1:9);

¹H-NMR (DMSO-d₆): δ 3.93, 5.48, 6.38, 6.42-6.48, 6.54, 7.06, 7.37, 7.49,8.44.

Example 26N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3-fluorophenyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 5 usingthe compound produced in Example 25 and the compound produced in Example4.

TLC: Rf 0.17 (hexane:ethyl acetate=1:9);

¹H-NMR (CDCl₃): δ 2.06-2.20, 2.54-2.68, 4.06, 6.43, 7.15-7.47,7.57-7.74, 7.94, 8.48, 9.32, 11.55.

Examples 26(1) to 26(3)

The following Example compounds were obtained by the procedure havingthe same purpose as in Example 26, using a carboxylic acid derivativewas used in place of the compound produced in Example 4.

Example 26(1)N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3-fluorophenyl}-1-(2,2-dimethylpropyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.36 (ethyl acetate);

¹H-NMR (DMSO-d₆): δ 0.99, 2.00-2.16, 2.54-2.60, 3.11-3.24, 3.94, 4.28,6.47, 7.40-7.57, 8.05, 8.47, 8.84, 11.81.

Example 26(2)N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3-fluorophenyl}-1-(3-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.32 (ethyl acetate);

¹H-NMR (CDCl₃): δ 2.07-2.21, 2.51-2.71, 4.05, 4.06, 6.39-6.45,7.01-7.13, 7.15-7.23, 7.29-7.40, 7.42, 7.57, 7.60-7.74, 7.85-8.00, 8.48,9.33, 11.38-11.49.

Example 26(3)N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3-fluorophenyl}-2′,5′-dioxo-1′-phenyl-2′,5′,6′,8′-tetrahydro-1′H-spiro[cyclopropane-1,7′-quinoline]-3′-carboxamide

TLC: Rf 0.33 (ethyl acetate);

¹H-NMR (CDCl₃): δ 0.32-0.44, 0.50-0.61, 2.40, 2.48, 4.05, 4.06, 6.42,7.14-7.25, 7.34-7.40, 7.42, 7.58, 7.59-7.70, 7.93, 8.49, 9.37, 11.54.

Example 27 4-[(6-chloro-3-pyridinyl)oxy]-6,7-dimethoxyquinazoline

Under argon atmosphere, DMAP (4.4 g) was added to4-chloro-6,7-dimethoxyquinazoline (8.0 g) and a DMSO suspension (20 mL)of 6-chloropyridine-3-ol (4.6 g), heated and stirred at a bathtemperature (80° C.) for two hours, and left to cool to roomtemperature. Thereafter, the reaction solution was diluted with ethylacetate, and washed with water and saturated sodium hydrogen carbonateaqueous solution. The organic layer was dried over anhydrous sodiumsulfate, and concentrated. The resulting residue was washed withhexane-ethyl acetate (3:1) to obtain the title compound (9.1 g) havingthe following physical property values.

TLC: Rf 0.16 (hexane:ethyl acetate=1:1);

¹H-NMR (DMSO-d₆): δ 3.97, 3.99, 7.41, 7.58, 7.69, 7.97, 8.50, 8.57.

Example 28 5-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-pyridinaminehydrochloride

Under argon atmosphere, 1.0 mol/L LHMDS (4.7 mL),tris(dibenzylideneacetone)dipalladium(0) chloroform complex (140 mg),and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (170 mg) were addedto a THF solution (15 mL) of the compound produced in Example 27 (1.0g). The mixture was stirred at a bath temperature (70° C.) for fourhours. After the reaction solution was left to cool to room temperature,and placed into ice water, followed by extraction with ethyl acetate.The organic layer was washed with water, dried over anhydrous sodiumsulfate, and concentrated. The resulting residue was suspended inacetonitrile (30 mL), and 2.0 mol/L hydrochloric acid (10 mL) was addedthereto and stirred at room temperature for 30 min. Precipitatesgenerated in the reaction solution were collected by filtration toobtain the title compound (591 mg) having the following physicalproperty values.

TLC: Rf 0.16 (ethyl acetate:methanol=10:1);

¹H-NMR (DMSO-d₆): δ 3.96, 3.99, 4.24, 7.10, 7.42, 7.53, 8.00-8.20, 8.07,8.20, 8.61.

Example 29N-{5-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 5 usingthe compound produced in Example 28 and the compound produced in Example4.

TLC: Rf 0.75 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 2.11, 2.59, 4.07, 7.26, 7.33, 7.54, 7.58-7.69, 8.27,8.52, 8.61, 9.33, 11.91.

Examples 29(1) to 29(6)

The following Example compounds were obtained by the procedure havingthe same purpose as in Example 27→Example 28→Example 29, usingcorresponding quinoline derivatives in place of4-chloro-6,7-dimethoxyquinazoline, 6-chloropyridine-3-ol, and thecompound produced in Example 4 or corresponding carboxylic acidderivatives in place of it.

Example 29(1)N-{5-[(7-methoxy-4-quinazolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

(LC-MS/ELSD): (retention time: 0.99 min);

¹H-NMR (CDCl₃): δ 2.02-2.21, 2.57, 3.99, 7.24-7.25, 7.27-7.29,7.30-7.33, 7.55-7.69, 8.23, 8.26, 8.51, 8.67, 9.33, 11.89.

Example 29(2)1-cyclobutyl-N-{5-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.47 (ethyl acetate:methanol=10:1);

1H-NMR (CDCl₃): δ 1.75-1.95, 1.96-2.10, 2.11-2.25, 2.40-2.54, 2.55-2.65,2.92-3.16, 4.08, 4.09, 4.74-4.93, 7.34, 7.56, 7.68, 8.36, 8.56, 8.62,9.16, 12.13.

Example 29(3)N-{5-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-pyridinyl}-1-(2,2-dimethylpropyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.44 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 1.06, 2.18-2.27, 2.63, 3.02-3.18, 4.08, 4.09, 7.34,7.56, 7.69, 8.36, 8.56, 8.61, 9.22, 12.17.

Example 29(4)N-{5-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-pyridinyl}1-[(2S)-1-hydroxy-3-methyl-2-butanyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.38 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 0.74, 1.13, 2.09-2.34, 2.41-2.72, 2.77-3.39,3.90-4.20, 4.07, 4.09, 4.44-4.69, 7.32, 7.55, 7.70, 8.32, 8.53, 8.60,9.15, 12.07.

Example 29(5)N-{5-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-pyridinyl}-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.55 (hexane:ethyl acetate=1:9, NH silica);

¹H-NMR (CDCl₃): δ 2.12, 2.56-2.63, 4.07, 7.23-7.35, 7.53, 7.66, 8.26,8.50, 8.60, 9.30, 11.84.

Example 29(6)N-{5-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-pyridinyl}-1-[(2R)-1-hydroxy-3-methyl-2-butanyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.20 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 0.72, 1.11, 2.22, 2.52, 2.94, 3.34, 4.07, 4.08, 4.16,4.40, 4.72, 7.27, 7.54, 7.72, 8.24, 8.45, 8.56, 8.86, 91.5, 12.14.

Example 30 4-(2-fluoro-4-nitrophenyl)-7-methoxyquinazoline

4-chloro-7-methoxy-quinazoline (50 mg) and 2-fluoro-4-nitrophenol (60mg) were added to diphenyl ether (10 mL), and the mixture was stirred at150° C. for two hours by using microwave. The reaction solution wascooled, and water was added. Thereafter, the water layer was extractedwith ethyl acetate, and the combined organic layer was washed with asaturated saline solution, and then concentrated. The resulting residuewas purified by silica gel column chromatography (hexane:ethylacetate=100:0→0:100) to obtain the title compound (60 mg) having thefollowing physical property values.

MASS (ESI, Pos.): 286 (M+H)⁺.

Example 31 3-fluoro-4-[7-methoxyquinazoline-4-yl)oxy]aniline

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 25,using the compound produced in Example 30.

¹H-NMR (CDCl₃): δ 3.70, 3.98, 6.49-6.57, 7.06, 7.24-7.30, 8.25, 9.47.

Example 32N-{3-fluoro-4-[(7-methoxy-4-quinazolinyl)oxy]phenyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 5, usingthe compound produced in Example 31 and the compound produced in Example4.

(LC-MS/ELSD): (retention time: 1.02 min);

¹H-NMR (CDCl₃): δ 2.06-2.20, 2.53-2.68, 3.98, 7.19-7.44, 7.58-7.73,7.93, 8.25, 8.67, 9.32, 11.51.

Example 33 tert-butyl [4-(quinazoline-4-yloxy)phenyl]carbamate

4-chloro-quinazoline (0.95 g), calcium carbonate (3.5 g), and(4-hydroxy-phenyl)-carbamic acid tert-butyl ester (0.90 g) were added toacetonitrile (10 mL), and the mixture was stirred at 100° C. for threehours. Water was added to the reaction solution, and the water layer wasextracted with ethyl acetate. The combined organic layer was washed witha saturated saline solution, and then concentrated. The resultingresidue was purified by silica gel column chromatography (hexane:ethylacetate=100:0→0:100) to obtain the title compound (1.3 g) having thefollowing physical property values.

¹H-NMR (CDCl₃): δ 1.53, 6.63, 7.18-7.20, 7.47, 7.64-7.68, 7.89-7.93,8.00, 8.37, 8.76.

Example 34 4-(quinazoline-4-yloxy)aniline hydrochloride

4 mol/L hydrochloric acid-1,4-dioxane solution (5 mL) was added to a THFsolution (5 mL) of the compound produced in Example 33 (100 mg), and themixture was stirred at room temperature for three hours. The reactionsolution was concentrated to obtain the title compound (81 mg) havingthe following physical property value.

MASS (ESI, Pos.): 238 (M+H)⁺.

Example 352,5-dioxo-1-phenyl-N-[4-(4-quinazolinyloxy)phenyl]-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 5, usingthe compound produced in Example 34 and the compound produced in Example4.

(LC-MS/ELSD): (retention time: 0.98 min);

¹H-NMR (CDCl₃): δ 2.08-2.13, 2.54-2.63, 7.21-7.29, 7.60-7.68, 7.82-7.84,7.91-7.93, 8.00, 8.37, 8.76, 9.34, 11.43.

Example 365-{[(3-hydroxy-4-methoxyphenyl)amino]methylene}-2,2-dimethyl-1,3-dioxane-4,6-dione

Under argon atmosphere, a methyl orthoformate (50 mL) solution ofmeldrum's acid (8.0 g) was heated at 100° C. for 5 min, and then3-hydroxy-4-methoxyaniline (7.0 g) was added to the solution, and theresulting solution was heated and stirred at 105° C. for 25 min. Theheating was stopped to cool with water, and precipitated powder wascollected by filtration, washed with methyl orthoformate and MTBE, anddried under reduced pressure to obtain the title compound (12.3 g)having the following physical property values.

TLC: Rf 0.25 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 1.75, 3.92, 5.82, 6.73, 6.84-6.88, 8.53, 11.2.

Example 375-({[3-(benzyloxy)-4-methoxyphenyl]amino}methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

Under argon atmosphere, the compound produced in Example 36 (12.0 g) wasdissolved in DMA (80 mL) at 50° C. The temperature was returned to roomtemperature. Then, potassium carbonate (7.35 g) and benzyl bromide (8.75g) were added thereto. The resulting solution was heated and stirred at60° C. for two hours. The mixture was left to cool to room temperature,and the solvent was concentrated, followed by adding ethyl acetate andwater and shaking thereof. Since deposits were precipitated, thedeposits were collected by filtration, washed with water and ethylacetate, and dried under reduced pressure to obtain the title compound(8.0 g) having the following physical property values.

TLC: Rf 0.49 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 1.75, 3.90, 5.17, 6.76-6.85, 6.91, 7.30-7.48, 8.48,11.2.

Example 38N-[5-({6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example11→Example 12→Example 13→Example 14→Example 15→Example 16→Example 17,using the compound produced in Example 37.

TLC: Rf 0.20 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 2.08-2.19, 2.45-2.64, 3.73, 4.02, 4.27, 6.43, 7.25,7.43, 7.52-7.65, 8.21, 8.47, 8.49, 9.32, 11.92.

Examples 38(1) to 38(7)

The following Example compounds were obtained by the procedure havingthe same purpose as in Example 38, using a corresponding compound inplace of the compound produced in Example 37.

Example 38(1)N-(5-{[7-(3-hydroxy-3-methylbutoxy)-6-methoxy-4-quinolinyl]oxy}-2-pyridinyl)-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.20 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.34, 2.07-2.15, 2.56-2.64, 3.28, 4.01, 4.43, 6.45,7.25, 7.43, 7.53-7.67, 8.21, 8.48, 8.51, 9.33, 11.93.

Example 38(2)N-[5-({6-methoxy-7-[3-(1-piperidinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.28 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.42, 1.52-1,64, 2.08-2.15, 2.38-2.45, 2.50-2.63,4.02, 4.24, 6.42, 7.21-7.28, 7.42, 7.51, 7.55-7.66, 8.21, 8.47, 8.49,9.32, 11.92.

Example 38(3)N-[5-({6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.25 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.79, 2.15, 2.56, 2.67, 4.02, 4.27, 6.42, 7.25, 7.42,7.51, 7.53-7.65, 8.21, 8.47, 8.49, 9.32, 11.92.

Example 38(4)N-[5-({6-methoxy-7-[3-(1-piperazinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.20 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 2.10, 2.55, 2.71, 3.15, 4.01, 4.26, 6.44, 7.26, 7.42,7.51-7.67, 8.21, 8.49, 9.31, 11.92.

Example 38(5)N-(5-{[7-(2-butyn-1-yloxy)-6-methoxy-4-quinolinyl]oxy}-2-pyridinyl)-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.56 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 1.86, 2.00-2.21, 2.48-2.74, 4.04, 4.90, 6.45,7.22-7.31, 7.50-7.68, 8.22, 8.45-8.54, 9.33, 11.94.

Example 38(6)N-[5-({6-methoxy-7-[3-(methylsulfonyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.16 (ethyl acetate:methanol=10:1, NH silica);

¹H-NMR (CDCl₃): δ 2.02-2.19, 2.40-2.68, 2.99, 3.29-3.40, 4.02, 4.32,6.45, 7.22-7.29, 7.40, 7.49-7.69, 8.22, 8.44-8.55, 9.33, 11.94.

Example 38(7)N-[5-({6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.20 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 2.13, 2.29, 2.48-2.65, 4.02, 4.25, 6.42, 7.21-7.28,7.42, 7.51, 7.52-7.67, 8.21, 8.47, 8.49, 9.32, 11.92.

Example 39N-[5-({7-[(3-methyl-2-buten-1-yl)oxy]-4-quinolinyl}oxy)-2-pyridinyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

Under argon atmosphere, cesium carbonate (94 mg) and1-bromo-3-methyl-2-butene (140 mg) were added to a DMF solution (15 mL)of the compound produced in Example 16 (100 mg), and the mixture wasstirred at a bath temperature (−10° C.) for two hours. An ammoniumchloride aqueous solution was added to the reaction solution, followedby extraction with ethyl acetate. The organic layer was washed with asaturated saline solution, dried over anhydrous sodium sulfate, andconcentrated, followed by purification by silica gel columnchromatography (hexane:ethyl acetate=1:4, NH silica) to obtain the titlecompound (55 mg).

TLC: Rf 0.30 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.79, 1.82, 2.08-2.17, 2.46-2.63, 4.67, 5.57, 6.39,7.23-7.26, 7.46, 7.48-7.65, 8.18, 8.22, 8.45, 8.49, 9.29, 11.90.

Example 40N-{5-[(7-{[(2R)-2,3-dihydroxy-3-methylbutyl]oxy}-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

Under argon atmosphere, tert-buthyl alcohol (0.5 mL), water (0.5 mL),AD-mix-β (50 mg), and methane sulfonamide (7 mg) were added to adichloromethane solution (0.5 mL) of the compound produced in Example 39(20 mg), and the mixture was stirred at room temperature for six hours.A sodium thiosulfate aqueous solution was added to the reactionsolution, followed by extraction with ethyl acetate. The organic layerwas washed with a saturated saline solution, dried over anhydrous sodiumsulfate, and concentrated, followed by purification by silica gel columnchromatography (ethyl acetate, NH silica) to obtain the title compound(3 mg).

TLC: Rf 0.10 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.32, 1.36, 2.11, 2.37, 2.60, 2.87, 3.92, 4.20, 4.32,6.42, 7.23, 7.43, 7.53-7.66, 8.20, 8.23, 8.48, 8.60, 9.32, 11.93.

Examples 40(1) to 40(6)

The following Example compounds were obtained by the procedure havingthe same purpose as in Example 39→Example 40, using a correspondingcompound in place of the compound produced in Example 16,1-bromo-3-methyl-2-butene, and AD-mix-β or AD-mix-α.

Example 40(1)N-{5-[(7-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.41 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 1.32, 1.36, 1.99-2.19, 2.50-2.68, 3.04, 3.15-3.23,3.74-3.90, 4.01, 4.21-4.33, 4.37-4.48, 6.45, 7.24-7.29, 7.42, 7.54,7.54-7.69, 8.18-8.23, 8.46-8.52, 9.32, 11.93.

Example 40(2)N-{5-[(7-{[(2R)-2,3-dihydroxy-3-methylbutyl]oxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.28-1.32, 2.07-2.15, 2.56-2.64, 2.90-3.40, 3.85,4.01, 4.27, 4.43, 6.45, 7.25-7.29, 7.42, 7.53-7.66, 8.21, 8.48, 8.50,9.32, 11.93.

Example 40(3)N-{5-[(7-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2,2-dimethylpropyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.41 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 1.06, 1.33, 1.37, 2.11-2.33, 2.55-2.71, 3.04,3.06-3.15, 3.16-3.24, 3.79-3.91, 4.03, 4.21-4.33, 4.39-4.48, 6.46, 7.43,7.53-7.61, 8.27-8.33, 8.48-8.56, 9.22, 12.18.

Example 40(4)N-{5-[(7-{[(2R)-2,3-dihydroxy-3-methylbutyl]oxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2,2-dimethylpropyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.06, 1.33-1.37, 2.18-2.26, 2.63, 3.00-3.20, 3.87,4.02, 4.28, 4.44, 6.46, 7.43, 7.55-7.60, 8.30, 8.49-8.55, 9.21, 12.18.

Example 40(5)N-{5-[(7-{[(2R)-2,3-dihydroxy-3-methylbutyl]oxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2′,5′-dioxo-1′-phenyl-2′,5′,6′,8′-tetrahydro-1′H-spiro[cyclopropane-1,7′-quinoline]-3′-carboxamide

TLC: Rf 0.49 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 0.37-0.40, 0.53-0.56, 1.32-1.36, 2.41, 2.48, 2.98,3.19, 3.85, 4.01, 4.27, 4.43, 6.46, 7.21-7.24, 7.42, 7.54-7.65, 8.22,8.49-8.52, 9.36, 11.94.

Example 40(6)N-{5-[(7-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(3-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.56 (ethyl acetate:methanol=10:1, DNH silica);

¹H-NMR (CDCl₃): δ 1.32, 1.36, 2.05-2.22, 2.53-2.71, 2.98-3.09,3.11-3.26, 3.77-3.92, 4.01, 4.20-4.30, 4.39-4.47, 6.45, 7.00-7.13,7.28-7.36, 7.42, 7.51-7.69, 8.23, 8.45-8.54, 9.32, 11.86.

Example 41bis(2-methyl-2-propanyl)(5-{[7-benzyloxy)-6-methoxy-4-quinolinyl]oxy}-2-pyridinyl)imidodicarbonate

5-{[7-(benzyloxy)-6-methoxy-4-quinolinyl]oxy}-2-pyridinamine (1.6 g) wasdissolved in a 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinonesolution (15 mL) of di-tert-butyl dicarbonate (CAS registration No.:24424-99-5) (3.95 mL). Triethyl amine (9.37 mL) and DMAP (52 mg) wereadded to the resulting solution, and the solution was stirred at roomtemperature for five hours. The reaction solution was diluted withhexane:ethyl acetate mixed solution (1:3), and washed with water. Then,the organic layer was concentrated, and purified by silica gel columnchromatography (hexane:ethyl acetate=4:1→0:1→ethylacetate:methanol=50:1→20:1) to obtain the title compound (2.4 g) havingthe following physical property values.

TLC: Rf 0.51 (ethyl acetate);

¹H-NMR (CDCl₃): δ 1.49, 4.04, 5.33, 6.45, 7.30-7.43, 7.44-7.62, 8.41,8.50.

Example 42 bis(2-methyl-2-propanyl){5-[(7-hydroxy-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}imidodicarbonate

Under argon atmosphere, ethyl acetate (10 mL) and ethanol (30 mL) wereadded to and dissolved in the compound produced in Example 41 (1.4 g).Palladium hydroxide (20 wt %, 420 mg) was added thereto, and the mixturewas stirred under hydrogen atmosphere at room temperature for fivehours. Palladium hydroxide was removed through Celite, and the filtratewas concentrated to obtain the title compound (1.2 g).

TLC: Rf 0.49 (ethyl acetate);

¹H-NMR (CDCl₃): δ 1.50, 4.08, 6.44, 7.36, 7.46-7.60, 8.42, 8.53.

Example 43 bis(2-methyl-2-propanyl)[5-({6-methoxy-7-[(3-methyl-3-buten-1-yl)oxy]-4-quinolinyl}oxy)-2-pyridinyl]imidodicarbonate

3-methyl-3-buten-1-ol (231 mg), N,N,N′,N′-tetramethyl azodicarboxamide(TMAD) (462 mg), and tri-n-butylphosphine (544 mg) were added to a THFsuspension (20 mL) of the compound produced in Example 42 (500 mg), andthe mixture was stirred at room temperature for three hours. Thereaction solution was diluted with ethyl acetate, and concentrated byremoving insoluble matters. The resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=3:2→0:1) to obtain thetitle compound (570 mg) having the following physical property values.

TLC: Rf 0.52 (hexane:ethyl acetate=3:7);

¹H-NMR (CDCl₃): δ 1.49, 1.86, 2.68, 4.03, 4.33, 4.76-4.99, 6.46, 7.35,7.45, 7.50, 7.55, 8.42, 8.52.

Example 44 bis(2-methyl-2-propanyl) {5-[{7-[(3S)-3,4-dihydroxy-3-methylbutoxy]-6-methoxy-4-quinolinyl}oxy]-2-pyridinyl}imidodicarbonate

Dichloromethane:t-butanol:water=1:1:1 (1.5 mL) was added to anddissolved in the compound produced in Example 43 (170 mg), AD-mix-β (431mg) and methane sulfonamide (58 mg) were added thereto, and the mixturewas stirred at room temperature overnight. The reaction solution wasdiluted with ethyl acetate, and washed with water. The organic layer wascollected and purified by silica gel column chromatography (hexane:ethylacetate=4:1→0:1→ethyl acetate:methanol=9:1) to obtain the title compound(152 mg) having the following physical property values.

TLC: Rf 0.54 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.29, 1.50, 2.06-2.17, 2.19-2.36, 2.90-3.32,3.45-3.65, 4.02, 4.28-4.51, 6.48, 7.36, 7.45, 7.51, 7.56, 8.42, 8.52.

Example 454-(4-{4-[(6-amino-3-pyridinyl)oxy]-6-methoxy-7-quinolinyl}oxy)-(2S)-2-methyl-1,2-butanediol

Trifluoroacetic acid (2 mL) was added to a dichloromethane solution (5mL) of the compound produced in Example 44 (152 mg). The mixture wasstirred at room temperature for two hours. The reaction solution wasconcentrated, and subjected to azeotrope with toluene twice. Theresulting residue was purified by silica gel column chromatography (NHsilica, ethyl acetate:methanol=9:1) to obtain the title compound (100mg) having the following physical property values.

TLC: Rf 0.35 (dichloromethane:methanol=9:1, NH silica);

¹H-NMR (CDCl₃): δ 1.28, 2.01-2.15, 2.17-2.34, 2.74-2.94, 3.08-3.23,3.44-3.66, 4.03, 4.26-4.46, 4.52, 6.43, 6.61, 7.31, 7.41, 7.56, 8.03,8.48.

Example 46 N-{5-[(7-{[(3S)-3,4-dihydroxy-3-methylbutyl]oxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 5, usingthe compound produced in Example 45 and the compound produced in Example4.

TLC: 0.43 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 1.28, 2.05-2.30, 2.56-2.64, 2.70-3.30, 3.48-3.60,4.02, 4.31-4.45, 6.45, 7.25-7.28, 7.33, 7.43-7.67, 8.21, 8.48-8.51,9.32, 11.93.

Examples 46(1) to 46(3)

The following Example compounds were obtained by the procedure havingthe same purpose as in Example 46, using the compound produced inExample 45, or a compound produced by subjecting the compound producedin Example 43 to the procedure having the same purpose as in Example44→Example 45 using AD-mix-α in place of AD-mix-β, and the compoundproduced in Example 4 or a corresponding carboxylic acid derivative inplace of it.

Example 46(1)N-{5-[(7-{[(3R)-3,4-dihydroxy-3-methylbutyl]oxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: 0.40 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 1.28, 1.97-2.17, 2.18-2.35, 2.52-2.69, 2.74-2.89,3.13, 3.40-3.69, 4.02, 4.23-4.52, 6.45, 7.20-7.30, 7.42, 7.53,7.54-7.70, 8.21, 8.45-8.52, 9.32, 11.93.

Example 46(2) N-{5-[(7-{[(3S)-3,4-dihydroxy-3-methylbutyl]oxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2′,5′-dioxo-1′-phenyl-2′,5′,6′,8′-tetrahydro-1′H-spiro[cyclopropane-1,7′-quinoline]-3′-carboxamide

TLC: 0.45 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 0.37-0.41, 0.53-0.56, 1.28, 2.05-2.30, 2.42, 2.48,2.70-3.30, 3.48-3.60, 4.02, 4.31-4.45, 6.45, 7.21-7.24, 7.42, 7.48-7.65,8.21, 8.48-8.51, 9.36, 11.93.

Example 46(3)N-{5-[(7-{[(3R)-3,4-dihydroxy-3-methylbutyl]oxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2′,5′-dioxo-1′-phenyl-2′,5′,6′,8′-tetrahydro-1′H-spiro[cyclopropane-1,7′-quinoline]-3′-carboxamide

TLC: 0.50 (ethyl acetate:methanol=10:1, NH silica);

¹H-NMR (CDCl₃): δ 0.33-0.43, 0.50-0.61, 1.28, 1.98-2.14, 2.16-2.33,2.42, 2.48, 2.73-2.91, 3.08-3.18, 3.42-3.68, 4.02, 4.23-4.51, 6.46,7.19-7.25, 7.42, 7.54, 7.55-7.66, 8.22, 8.46-8.54, 9.36, 11.94.

Example 47(5E)-5-(hydroxyimino)-4-methyl-2-oxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxylic acid

A pyridine solution (1.0 mL) of the compound produced in Example 4 (142mg) and hydroxylamine hydrochloride (208 mg) was heated and refluxed forone hour. The solution was cooled to room temperature. The reactionsolution was diluted with ethyl acetate and washed with 1 mol/Lhydrochloric acid. The obtained organic layer was concentrated to obtainthe title compound (151 mg) having the following physical propertyvalues.

TLC: Rf 0.42 (dichloromethane:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 1.63-1.81, 2.26-2.36, 2.60, 7.38-7.46, 7.51-7.68,8.90, 11.30, 14.03.

Example 48N-{(5E)-5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-5-(hydroxyimino)-2-oxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wereobtained by the procedure having the same purpose as in Example 5, usingthe compound produced in Example 47 and the compound produced in Example2.

TLC: 0.15 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.77-1.94, 2.38, 2.77, 4.05, 6.46, 7.20-7.25, 7.43,7.50-7.65, 7.99-8.07, 8.22, 8.48, 8.52, 9.33, 12.23.

Example 48(1)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-(5E)-5-(methoxyimino)-2-oxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 48,using a corresponding carboxylic acid derivative in place of thecompound produced in Example 47 and the compound produced in Example 2.

TLC: 0.18 (ethyl acetate);

¹H-NMR (CDCl₃): δ 1.74-1.92, 2.29-2.40, 2.62-2.75, 4.00, 4.05, 6.45,7.20-7.28, 7.42, 7.50-7.66, 8.20-8.24, 8.46-8.52, 9.36, 12.26.

Example 49 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinoline

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 24,using 7-benzyloxy-6-methoxy-quinoline-4-ol in place of 6,7-dimethoxyquinoline-4-ol.

TLC: Rf 0.76 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 4.03, 5.34, 6.54, 7.28-7.43, 7.45, 7.47-7.55,8.10-8.15, 8.19, 8.56.

Example 50 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-quinolinolhydrobromate

5.1 mol/L hydrobromic acid-acetic acid solution (10 mL) was added to thecompound produced in Example 49 (1.6 g). The mixture was stirred at roomtemperature for five hours. MTBE (50 mL) was added to the reactionsolution, and the resulting solution was stirred. Generated precipitateswere collected by filtration to obtain the title compound (1.5 g) havingthe following physical property values.

¹H-NMR (CD₃OD): δ 4.14, 7.05, 7.43, 7.76-7.85, 7.86, 8.30-8.38,8.39-8.46, 8.69.

Example 514-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-[3-(4-morpholinyl)propoxy]quinoline

Cesium carbonate (4.0 g) and 4-(3-chloropropyl)morpholine (517 mg) wereadded to a DMF solution (9.8 mL) of the compound produced in Example 50(1.0 g), and the mixture was stirred at 60° C. for 16 hours. The mixturesolution was diluted with ethyl acetate, and washed with water. Thewater layer was extracted with ethyl acetate twice. The combined organiclayer was dried over anhydrous sodium sulfate and concentrated. Theresulting residue was purified by silica gel column chromatography (NHsilica, hexane:ethyl acetate=1:1-0:1) to obtain the title compound (600mg) having the following physical property values.

TLC: Rf 0.50 (ethyl acetate, NH silica);

¹H-NMR (DMSO-d₆): δ 1.90-2.07, 2.32-2.43, 3.25-3.35, 3.48-3.64, 3.92,4.21, 6.77, 7.45, 7.55-7.67, 8.14-8.25, 8.41-8.50, 8.56.

Example 523-fluoro-4-{(6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl)oxy}aniline

Under argon atmosphere, the compound produced in Example 51 (300 mg) wasdissolved in ethyl acetate: ethanol=1:1 (30 mL), and palladium hydroxide(20 wt %, 99 mg) was added to the solution, and the argon atmosphere wasreplaced with a hydrogen atmosphere. After the solution was stirred atroom temperature for eight hours, the reaction solution was filteredthrough Celite, and the filtrate was concentrated to obtain the titlecompound (240 mg) having the following physical property values.

¹H-NMR (CDCl₃): δ 2.03-2.23, 2.43-2.53, 2.57, 3.66-3.77, 3.86, 4.03,4.26, 6.40, 6.45-6.61, 7.03, 7.42, 7.58, 8.46.

Example 53N-[3-fluoro-4-({6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl}oxy)phenyl]-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 5, usingthe compound produced in Example 52 and the compound produced in Example2.

TLC: Rf 0.71 (ethyl acetate:methanol=10:1, NH silica);

¹H-NMR (DMSO-d₆): δ 1.88-2.07, 2.34-2.41, 2.41-2.46, 2.51-2.57,3.31-3.37, 3.52-3.64, 3.94, 4.20, 6.42-6.49, 7.39, 7.40-7.53, 7.54-7.71,8.04, 8.46, 8.95, 11.64.

Example 54 methyl2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

2-oxo-1,5,6,7-tetrahydro-cyclopenta[b]pyridine-3-carboxylic acid (CASregistration No.: 115122-63-9) (200 mg) was dissolved in methanol (20mL) at room temperature, and concentrated sulfuric acid (0.006 mL) wasadded to the solution. The mixture was stirred at a bath temperature(70° C.) for four hours. The solution was left to cool to roomtemperature, the solvent was distilled off under reduced pressure, and asodium hydrogen bicarbonate aqueous solution and dichloromethane wereadded thereto, and the solution was separated. The organic layer waswashed with a saturated saline solution, and then was dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure to obtain the title compound (155 mg) having thefollowing physical property values.

TLC: Rf 0.21 (ethyl acetate);

¹H-NMR (CDCl₃): δ 2.13-2.20, 2.80-2.84, 2.97-3.03, 3.91, 8.10.

Example 55 methyl2-oxo-1-phenyl-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

The compound produced in Example 54 (140 mg) was dissolved indichloromethane (7 mL) at room temperature. Phenylboronic acid (220 mg),copper acetate (263 mg), and pyridine (0.234 mL) were added to thesolution, and the solution was stirred for 20 hours. The solution wasfiltered through a glass filter, and the solvent was distilled off underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=8:2→ethyl acetate) to obtainthe title compound (131 mg) having the following physical propertyvalues.

TLC: Rf 0.51 (ethyl acetate);

¹H-NMR (CDCl₃): δ 2.02-2.12, 2.53-2.58, 2.83-2.88, 3.88, 7.20-7.23,7.44-7.53, 8.21.

Example 562-oxo-1-phenyl-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylicacid

The compound produced in Example 55 (120 mg) was dissolved in methanol(2 mL) at room temperature. 2 mol/L sodium hydroxide aqueous solution(0.891 mL) was added to the solution, and the solution was stirred forone hour. 2N hydrochloric acid (0.891 mL) and ethyl acetate were addedto the reaction solution, and the solution was separated. The organiclayer was washed with a saturated saline solution, then was dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure to obtain the title compound (109 mg) having thefollowing physical property values.

TLC: Rf 0.64 (ethyl acetate);

¹H-NMR (CDCl₃): δ 2.09-2.19, 2.63-2.68, 2.92-2.97, 7.25-7.30, 7.52-7.62,8.51, 14.24.

Example 57N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2-oxo-1-phenyl-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 5, usingthe compound produced in Example 56 and the compound produced in Example2.

TLC: Rf 0.65 (ethyl acetate:methanol=9:1);

¹H-NMR (DMSO-d₆): δ 2.03-2.13, 2.60-2.65, 2.92-2.97, 3.97, 3.99, 6.58,7.45, 7.47-7.52, 7.57, 7.58-7.68, 7.86-7.90, 8.38, 8.48, 8.53, 8.60,12.58.

Examples 57(1) to 57(2)

The Example compounds each having the following physical property valueswere obtained by the procedure having the same purpose as in Example55→Example 56→Example 57, using a corresponding derivative in place ofthe compound produced in Example 54 and the compound produced in Example2.

Example 57(1)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2-oxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.63 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.71-1.83, 2.20-2.29, 2.68-2.76, 4.05, 6.44,7.19-7.24, 7.42, 7.46-7.62, 8.21, 8.44-8.50, 12.51.

Example 57(2)N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-2,5,6,7-tetrahydro-1H-cyclopenta[b]piperidine-3-carboxamide

TLC: Rf 0.63 (ethyl acetate:methanol=9:1);

¹H-NMR (CDCl₃): δ 2.68-2.81, 4.05, 6.45, 7.35, 7.43, 7.53, 7.55-7.68,8.24, 8.49, 8.51, 9.03, 11.91.

Example 58N-{5-[(7-{[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]methoxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 17,using the compound obtained by subjecting the compound produced inExample 37 to procedure having the same purpose as in Example 11→Example12→Example 13→Example 14→Example 15→Example 16, and(S)-(2,2-dimethyl-1,3-dioxolane-4-yl)methanol.

TLC: Rf 0.60 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.42, 1.50, 2.11, 2.60, 4.01, 4.14-4.29, 4.64, 6.44,7.42, 7.52-7.65, 8.21, 8.47, 8.50, 9.32, 11.92.

Example 59N-{5-[(7-{[(2R)-2,3-dihydroxypropyl]oxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The compound produced in Example 58 (35 mg) was dissolved in THF (1 mL)at room temperature. Methanol (1 mL) and p-toluenesulfonic acidmonohydrate (3.0 mg) were added to the solution, and the mixture wasstirred room temperature for 16 hours. The reaction solution was dilutedwith ethyl acetate, and washed with water and a saturated sodiumhydrogen carbonate aqueous solution. The organic layer was dried overanhydrous sodium sulfate, and then concentrated. The resulting residuewas purified by silica gel chromatography (ethylacetate:methanol=100:0→70:30) to obtain the title compound (32 mg)having the following physical property values.

TLC: Rf 0.55 (ethyl acetate:methanol=5:1, NH silica);

¹H-NMR (CDCl₃): δ 2.11, 2.56-2.64, 3.89, 4.02, 4.21-4.36, 6.45,7.25-7.28, 7.44, 7.53-7.66, 8.21, 8.48-8.51, 9.32, 11.93.

Examples 59(1) to 59(3)

The following Example compounds were obtained by the procedure havingthe same purpose as in Example 59, using the compound produced inExample 58 or a corresponding compound in place of it.

Example 59(1)N-{5-[(7-{[(2S)-2,3-dihydroxypropyl]oxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.55 (ethyl acetate:methanol=5:1, NH silica);

¹H-NMR (CDCl₃): δ 2.11, 2.56-2.64, 3.90, 4.02, 4.21-4.36, 6.44,7.24-7.29, 7.44, 7.52-7.66, 8.22, 8.48-8.51, 9.33, 11.94.

Example 59(2)N-{5-[(7-{[(2S)-2,3-dihydroxypropyl]oxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2,2-dimethylpropyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.35 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.06, 2.22, 2.63, 3.09, 3.89, 4.02, 4.22, 4.34, 6.44,7.43, 7.55, 7.58, 8.30, 8.52, 8.54, 9.21, 12.18.

Example 59(3)N-{5-[(7-{[(2R)-2,3-dihydroxypropyl]oxy}-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-1-(2,2-dimethylpropyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

TLC: Rf 0.35 (ethyl acetate, NH silica);

¹H-NMR (CDCl₃): δ 1.06, 2.22, 2.63, 3.09, 3.89, 4.02, 4.22, 4.34, 6.44,7.43, 7.55, 7.58, 8.30, 8.52, 8.54, 9.21, 12.18.

Example 605-hydroxy-N-{5-[(7-hydroxy-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2-oxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example11→Example 12→Example 13→Example 14→Example 15→Example 16, using thecompound produced in Example 37.

TLC: Rf 0.26 (dichloromethane:methanol=19:1);

¹H-NMR (CDCl₃): δ 1.62-1.93, 2.27, 4.08, 4.85, 6.42, 7.23, 7.52-7.62,8.21, 8.46, 8.51, 8.80, 12.37.

Example 61N-{5-[(7-hydroxy-6-methoxy-4-quinolinyl)oxy]-2-pyridinyl}-2-oxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The compound produced in Example 60 (300 mg) was dissolved indichloromethane (5 mL). Triethylsilane (127 mg), and trifluoroaceticacid (0.081 mL) were added to the solution, sequentially. The solutionwas stirred at room temperature for 22 hours. The reaction solution wasdiluted with ethyl acetate, and washed with water and a saturated sodiumhydrogen carbonate aqueous solution. The organic layer was dried overanhydrous sodium sulfate, and then concentrated. The resulting residuewas purified by silica gel chromatography (hexane:ethylacetate=30:70→0:100) to obtain the title compound (183 mg) having thefollowing physical property values.

TLC: Rf 0.77 (ethyl acetate:methanol=5:1);

¹H-NMR (CDCl₃): δ 1.75, 2.23, 2.72, 4.08, 6.42, 7.22, 7.51-7.60, 8.21,8.44-8.51, 8.49, 12.51.

Example 62 4-methyl-7,8-dihydro-2H-chromene-2,5(6H)-dione

Ethyl acetoacetate (CAS registration No.: 141-97-9) (17.40 g),1,3-cyclohexanedione (CAS registration No.: 504-02-9) (10.00 g), DMAP(0.22 g), and pyridine (30 mL) were placed in a 200-mL eggplant flask,and stirred at a bath temperature (140° C.) for one day. After themixture was left to cool to room temperature, the solvent was distilledoff under reduced pressure. The resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) to obtain the titlecompound (4.50 g) having the following physical property values.

(LC-MS/ELSD): (retention time: 0.81 min);

¹H-NMR (CDCl₃): δ 2.11, 2.48, 2.57, 2.87, 5.99.

Example 63 3-bromo-4-methyl-7,8-dihydro-2H-chromene-2,5(6H)-dione

N-bromosuccinimide (CAS registration No.: 128-08-5) (2.00 g) was addedinto a DMF (40 mL) solution of the compound produced in Example 62 in a100-mL eggplant flask, and the solution was stirred at room temperaturefor one day. The solvent was distilled off under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=9:1) to obtain the title compound (1.16 g) havingthe following physical property values.

(LC-MS/ELSD): (retention time: 0.76 min);

¹H-NMR (CDCl₃): δ 2.12, 2.59, 2.69, 2.87.

Example 643-bromo-4-methyl-1-phenyl-7,8-dihydro-2,5(1H,6H)-quinolinedione

The compound produced in Example 63 (1.15 g) and aniline (1.25 g) wereplaced in a 30-mL eggplant flask. The mixture was stirred at a bathtemperature (70° C.) for 20 hours. 1 mol/L hydrochloric acid was addedto the reaction solution. The reaction solution was extracted with ethylacetate, washed with water and a saturated saline solution sequentiallyin this order, and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=7:3) to obtainthe title compound (1.31 g) having the following physical propertyvalues.

(LC-MS/ELSD): (retention time: 1.12 min);

¹H-NMR (CDCl₃): δ 1.96, 2.43, 2.54, 2.79, 7.16-7.20, 7.49-7.58.

Example 65 methyl4-methyl-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxylate

The compound produced in Example 64 (1.11 g), potassium acetate (0.66g), DMF (11 mL), and methanol (11 mL), and, after degassing,[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloridedichloromethane complex (1:1) [PdCl₂ (dppf)₂CH₂Cl₂] (0.27 g) were placedin a 200-mL eggplant flask. After replacement with carbon monoxide wascarried out, stirring at a bath temperature (70° C.) was carried out for17 hours. 1 mol/L hydrochloric acid was added to the reaction solution.The reaction solution was extracted with ethyl acetate, washed withwater and a saturated saline solution in this order, and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=7:3) to obtain the title compound(0.51 g) having the following physical property values.

(LC-MS/ELSD): (retention time: 0.75 min);

¹H-NMR (CDCl₃): δ 1.97, 2.48, 2.53, 2.56, 3.89, 7.17-7.20, 7.48-7.56.

Example 664-methyl-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydroquinoline-3-carboxylicacid

The compound produced in Example 65 (1.85 g) and 5 mol/L hydrochloricacid (19 mL) were placed in a 50-mL eggplant flask. The mixture wasstirred at a bath temperature (50° C.) for 26 hours. Precipitate wasremoved by filtration, and the filtrate solvent was distilled off underreduced pressure. The resulting residue was washed in a slurry form withmethanol and ethyl acetate to obtain the title compound (0.89 g) havingthe following physical property values.

(LC-MS/ELSD): (retention time: 0.66 min);

¹H-NMR (CD₃OD): δ 1.97, 2.54, 2.63, 7.29-7.32, 7.54-7.63.

Example 67N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-4-methyl-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 5, usingthe compound produced in Example 66 and the compound produced in Example2.

TLC: Rf 0.62 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 2.01, 2.53, 2.58, 2.86, 4.05, 6.42, 7.22, 7.42,7.49-7.61, 8.20, 8.45, 8.50, 9.73.

Example 67(1)N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl}-4-methyl-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide

The title compound having the following physical property values wasobtained by the procedure having the same purpose as in Example 67,using the compound produced in Example 66 and the compound produced inExample 22.

TLC: Rf 0.48 (ethyl acetate:methanol=19:1);

¹H-NMR (CDCl₃): δ 2.01, 2.52, 2.59, 2.93, 4.04, 6.45, 7.14, 7.23, 7.41,7.55-7.68, 7.72, 8.47, 9.79.

Experiment Example

Biological Examples are described below. Based on these experimentmethods, the effect of the compound of the present invention wasverified.

Biological Example 1 Measurement of an Axl Inhibitory Activity (In VitroTest)

An Axl enzyme inhibitory activity was measured by using LanthaScreen(registered trademark) system (Invitrogen) based on the attachedinstruction. The reagents used are shown below.

Reaction buffer solution: a solution containing 50 mmol/L HEPES (pH7.5),0.01% Brij35, 10 mmol/L MgCl₂ and 1 mmol/L EGTA was prepared by usingpurified water. Test substance solution: a solution containing a testcompound of 5-fold concentration with respect to the final concentrationwas prepared by 20-fold diluting a DMSO solution of test compound ofeach concentration with the reaction buffer solution.

Enzyme solution: a solution containing 400 ng/mL Axl enzyme was preparedby using the reaction buffer solution.

Substrate solution: a solution containing 45 mmol/L ATP and 500 nmmol/LFluorescein-Poly GT (Invitrogen) was prepared by using the reactionbuffer solution.

Detection solution: a solution containing 20 mM EDTA and 4 nM PY20(Invitrogen) was prepared by using Dilution B (Invitrogen).

A 10 mmol/L DMSO solution of the test compound was dispensed into a96-well plate (Nunc), and, furthermore, a 3-fold dilution series wasprepared using DMSO. In each well of the 96-well plate for measurement,5 μL each of the reaction buffer solution containing DMSO was added to aBlank group and a medium group, and 5 μL of the test substance solutionwas added to the test substance group, respectively. Next, 10 μL/well ofthe reaction buffer solution was added to the Blank group, and 10μL/well each of the enzyme solution was added to the medium group andthe test compound group, followed by stirring at room temperature for 10min. After the completion of stirring, 10 μL each of the substratesolution was added into each well, followed by stirring at roomtemperature with light shielded for one hour. After the completion ofreaction, 25 μL each of the detection solution was added to each well,and stood still at room temperature with light shielded for 30 min.After standing sill, fluorescence intensity at 520 nm and 495 nm at thetime of irradiation with exciting light of 340 nm was measured by usingAnalyst GT (Molecular Devices). The phosphorylation of the artificialsubstrate was quantified by Time-resolved Fluorescence Resonance EnergyTransfer (TR-FRET). TR-FRET ratio was calculated by dividing 520 nmfluorescence signal by 495 nm fluorescence signal for each well, and theinhibition rate (%) in the test compound group was calculated based onthe following mathematical formula.Inhibition rate (%)=[1−(TR-FRET ratio of test compoundgroup−A)/(B−A)×100  [Math. 1]A: average value of TR-FRET ratios of Blank groupB: average value of TR-FRET ratios of medium group

Values of 50% inhibition rate (IC50 values) of the test compound werecalculated from the inhibition curve based on the inhibition rate of thetest compounds in each concentration.

As a result, in the compounds of the present invention, IC50 values ofthe compound of, for example, Examples 5, 5(1), 5(6), 17(2), and 23(2)were 0.0022 μM, 0.0056 μM, 0.0043 μM, 0.0044 μM, and 0.0011 μM,respectively.

On the other hand, as comparative compounds, the Axl inhibitory activityof each of the compound of Example 8 described in Patent Literature 1(Comparative compound A) and the compound 2 of Example 3 described inPatent Literature 3 (Comparative compound B), having the followingstructures, was measured. In both cases, IC50 value was higher than 10μM.

Biological Example 2 Measurement of Proliferation Suppression Rate byUsing Mouse Pro-B Cell Line (Ba/F3 Axl) Stably Expressing Axl

A 0.1 mmol/L DMSO solution of the test compound was dispensed into a96-well plate, and a 3-fold dilution series was prepared using DMSO.DMSO solutions of test compounds, having various concentrations, werefurther 500-fold diluted with a RPMI1640 medium (containing 10% HI-FBS,1% penicillin) and a diluted solution of the test compound having500-fold concentration with respect to the final concentration wasprepared. In each well of the 96-well plate (BD Biosciences) formeasurement, 50 μL of a RPMI medium was added to the Blank group, 50 μLof a RPMI medium containing 0.2% DMSO was added to the medium group, and50 μL of the diluted solution of the test compound was added to the testcompound group, respectively. Ba/F3 Axl was diluted with a medium tohave a density of 2×10⁵ cells/mL to prepare a cell suspension. In eachwell of the 96-well plate for measurement, 50 μL each of the RPMI mediumwas added to the Blank group, and 50 μL each of the cell suspension tothe medium group and the test compound group, respectively, and thegroups were stood still at 37° C. at 5% CO₂ for 48 hours. After standingstill, Relative Light Unit (RLU) was measured by using CELLTITER-GLO(registered trademark) LUMINESCENT CELL VIABILITY ASSAY (Promega). Themeasurement was carried out according to the attached instruction. Toeach well, 100 μL each of light-emitting solution was added. The platewas stirred at room temperature for 3 min and then stool still at roomtemperature with light shielded for 10 min, and RLU was measured byusing Microplate Reader (SpectraMax M5e, Molecular Devices). The averagevalues of RLU of the Blank group and the medium group were respectivelycalculated, and the proliferation suppression rate of the test compoundgroup was calculated.Proliferation suppression rate (%)={1−(RLU of test compoundgroup−A)/(B−A)}×100  [Math. 2]A: average value of RLU of Blank groupB: average value of RLU of medium group

A value of 50% inhibition rate (IC50 value) of the test compound wascalculated from the inhibition curve based on the inhibition rate ineach concentration of the test compound.

As a result, in the compounds of the present invention, IC50 values ofthe compounds of, for example, Examples 5, 5(1), 5(6), 17(2), and 23(2)were 0.0007 μM, 0.0008 μM, 0.0078 μM, 0.0012 μM, and 0.0012 μM,respectively.

On the other hand, IC50 values of the comparative compounds A and B,were 0.62 μM and >10 μM, respectively.

Biological Example 3 Evaluation of Kinase Selectivity (In Vitro Test)

Similar to Biological Example 1, values of 50% inhibition rate (IC50value) with respect to various kinases (KDR, DDR1, FLT4, and ROS) of thetest compound were measured. The Axl selective inhibitory activity ofthe test compound with respect to kinases, for example, KDR, wascalculated based on the above-mentioned ratio of the IC50 values. Thecalculated values are shown in the following Table 1. As the testcompound, for the compound of the present invention, the compounds ofExamples 5, 5(1), 17(2), and 23(2) were used, and for the comparativecompounds, the compound of Example 5 (Comparative compound C) and thecompound of Example 92 (Comparative compound D) described in PatentLiterature 5, having the following structure, were used.

TABLE 1 KDR [IC50]/Axl [IC50] Example 5 about 900 times Example 5(1)about 1800 times Example 17(2) about 650 times Example 23(2) about 520times Comparative compound C about 0.2 times Comparative compound Dabout 28 times

Results showed that the compound of the present invention had Axlselective inhibition effect on KDR as compared with the comparativecompounds. KDR is kinase also referred to as vascular endothelial growthfactor receptor 2 (VEGF Receptor 2). It is known that inhibition of KDRmay cause a side effect of increasing blood pressure (Hypertension, vol.39, p. 1095-1100, 2002). Therefore, it was suggested that the compoundsof the present invention were excellent compounds capable of avoidingthe side effect, which was a problem in comparative compounds, forexample, hypertension. Furthermore, it has been also suggested that theother three types of kinases (DDR1, FLT4, and ROS) might cause sideeffect to be avoided, from the phenotype of the KO mouse or transgenicmouse. It became apparent that the compound of the present invention hasexcellent selectivity to such specific kinases and therefore capable ofavoiding side effect.

Biological Example 4 Measurement of Inhibitory Activity ofDrug-Metabolizing Enzyme (Human CYP2C8 Inhibition Effect)

The reaction was carried out in a 384-well plate. As the positivecontrol substance (CYP2C8: quercetin), a solution, which had beenadjusted with DMSO to have 300 times higher concentration than the finalconcentration (CYP2C8: 22.5 and 225 μmol/L) and been 75-fold dilutedwith purified water containing 2.7% acetonitrile, was prepared (CYP2C8:0.3 and 3 mol/L). The test compounds were prepared to have aconcentration of 0.3 and 3 mol/L with DMSO, and then 75-fold dilutedwith purified water containing 2.7% acetonitrile to be 4 and 40 μmol/L.Then, a reaction mixture solution was prepared by addition of apotassium phosphate buffer (pH 7.4), magnesium chloride (5 mol/L),substrate (CYP2C8: Luciferin-ME, 150 mol/L), and E. coli-expressed livermicrosome CYP2C8 (Cypex, 30 pmol/L) (the numerical values are finalconcentrations). The reaction was started by addition of 8 μL of thisreaction mixture, 4 μL each of the test compound and the positivecontrol solution which had been prepared as described above, and 4 μL ofNADPH production system solution (5.2 mM NADP, 13.2 mMglucose-6-phosphate, 1.6 U/mL glucose-6-phosphate dehydrogenase) andincubation was carried out at 37° C. for 30 min. Thereafter, 16 μL ofluciferase solution was added to stop the reaction and to allowluciferin to emit light, and the luminescence intensity of the reactionsolution was measured. The inhibition rate is a reduction rate(inhibition rate) of the luminescence intensity when compared with thecontrol in which the reaction was carried out by the addition of DMSO inplace of the test compound solution. The inhibition rate was calculatedfrom the following mathematical formula.Inhibition rate (%)=100−{(luminescence intensity of testcompound−background luminescence intensity)/(luminescence intensity ofcontrol−background luminescence intensity)×100}  [Math. 3]The IC50 value was defined to be <1 μM when the inhibition rate at 1μmol/L was not less than 50%; and >10 μM when the inhibition rate at 10μmol/L was not more than 50%. The range between the above-mentionedrange (not more than 50% at 1 μmol/L and not less than 50% at 10 μmol/L)was calculated using the following mathematical formula:IC50=(50−b)/a  [Math. 4]wherein a and b are the slope and intercept of the linear regressionline: y=ax+b that passes through the two points: the concentration andthe inhibition rate at 1 μmol/L and the concentration and the inhibitionrate at 10 μmol/L.

The IC50 values of the comparative compounds and compounds of thepresent invention were measured using the measurement method describedabove.

As a result, the IC50 value of CYP2C8 was 2.6 μM for the comparativecompound E (Example 133 described in Patent Literature 4). On the otherhand, for the compound of the present invention, the IC50 values ofCYP2C8 were >10 μM in the compounds of, for example, Examples 5, 5(1),17(2), and 23(2). Therefore, it was shown that the compound of thepresent invention had less CYP inhibition effect with respect to thecomparative compound.

FORMULATION EXAMPLE Formulation Example 1

The components indicated below were mixed by a standard method, followedby making the mixture into tablets to obtain 10,000 tablets eachcontaining 10 mg of active ingredient.

N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}- 100 g2,5-dioxo-1-phenyl-1,2,5,6,7,8- hexahydro-3-quinolinecarboxamide calciumcarboxymethyl cellulose (disintegrant)  20 g magnesium stearate(lubricant)  10 g microcrystalline cellulose 870 g

Formulation Example 2

The components indicated below were mixed by a standard method, filteredthrough a dust-removing filter, filled into ampoules so that each ampulecontains 5 ml, and thermally sterilized in an autoclave to obtain 10,000ampoules each containing 20 mg active ingredient.

N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}- 200 g7,7-dimethyl-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide mannitol  20 g distilled water  50 L

INDUSTRIAL APPLICABILITY

A compound of the present invention has a strong Axl inhibitoryactivity, and therefore, is useful for treatment for Axl-relateddiseases, for example, cancer, kidney diseases, immune system diseases,and circulatory system diseases.

The invention claimed is: 1.N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide,or a salt thereof. 2.N-{5-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide.